BRPI0621773A2 - use of a formulation comprising sulfoalkyl ether cyclodextrin and corticosteroids, and method for preparing said formulation - Google Patents

Abstract

USE OF A FORMULATION UNDERSTANDING SULFOalkyl ETH AND CORTICOSTEROID CYCLODEXTRIN, AND METHOD FOR THE PREPARATION OF THE FORMULATION. The present invention relates to an inhalable formulation that contains SAE-CD and corticosteroids. The formulation is adapted for administration to a patient by nebulization with any known nebulizer. The formulation can be included in a kit. The formulation is administered as an aqueous solution, however, it can be stored as a dry powder, ready-to-use solution, or concentrated composition. The formulation is used in an improved nebulization system to deliver corticosteroids by inhalation. SAE-CD present in a formulation significantly enhances the chemical stability of budesonide. A method of administering the formulation by inhalation is provided. A formulation can also be administered by conventional nasal delivery apparatus.

Description

Report of the Invention Patent for "USE OF A FORMULATION UNDERSTANDING SULPHALKYL AND CORTICOSTEROID Ether CYCLODEXTRIN, AND METHOD FOR PREPARING SUCH FORMULATION".

CROSS REFERENCE TO PREVIOUS PATENT APPLICATIONS

This patent application is a partial continuation and claims the priority of United States Patent Application No. 11 / 479,979 filed June 30, 2006.

FIELD OF INVENTION

The present invention relates to methods and systems for administering sulfoalkyl ether cyclodextrin and corticosteroid formulations such as budesonide by nebulization and inhalation. The invention also relates to methods of treating respiratory diseases and disorders of air passages.

BACKGROUND OF THE INVENTION

The distribution of a drug by inhalation allows the drug to be deposited in different sections of the respiratory tract, eg throat, trachea, bronchi and alveoli. Generally, the smaller the particle size, the longer the particle will remain suspended in air and the further the drug can be distributed to the respiratory tract. Corticosteroids are delivered by inhalation using nebulizers, metered dose inhalers, or dry powder inhalers. The main advantages of nebulizers over other methods of pulmonary installation are that patient co-operation is not required and larger doses of medication are easier to distribute. The main problems with nebulizers, however, are their increased cost, reduced portability, and lack of awareness of the need to prepare medication beforehand, and the increased time required to administer a treatment. A method of perfecting the administration of drugs such as corticosteroids by nebulization would be desired.

The cyclic budesonide ((R1S) -H β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetal with butyraldehyde; C 25 H 34 O 6; Mw: 430.5) is quite known. It is supplied commercially as a mixture of two isomers (22R and 22S). Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity. Budesonide administration is indicated for the maintenance treatment of asthma and as prophylactic therapy in children.

Budesonide commercial formulations are sold by AstraZeneca LP (Wilmington, DE) under the trademarks ENTOCORT® EC, PULMICORT RESPULES®, Rhinocort Aqua®, Rhinocort® Nasal Inhaler and Pulmicort Turbuhaler®, and under its generic name. PULMICORT RESPULS®, which is a sterile aqueous suspension of micronized budesonide, is administered by inhalation using a nebuliser, in particular a compressed air-powered jet nebulizer that distributes from 2 to 18% of the drug mass contained in nominal load. The general unit dose formulation of PULMICORT RESPULES is mentioned in United States Patent No. 6,598,603, and is an aqueous suspension wherein budesonide is suspended in an aqueous medium comprising about 0.05 to 1.0 mg budesonide. 0.05 to 0.15 mg NaEDTA, 8.0 to 9.0 mg NaCl, 0.15 to 0.25 mg polysorbate, 0.25 to 0.30 mg anhydrous citric acid, and 0, 45 to 0.55 mg of sodium citrate per ml of water. RHINOCORT® NASAL INHALER® is a metered dose pressurized aerosol unit containing a suspension of micronized budesonide in a propellant mixture. RHINOCORT® AQUA® is an odorless double-dose hand pump spray formulation containing a suspension of micronized budesonide in an aqueous medium. Suspensions should not be administered with an ultrasonic nebulizer.

A wide variety of nebulizers differing in operating mode are available, for example, jet nebulizers (optionally sold with compressors), ultrasonic nebulizers, vibrating membrane, vibrating mesh nebulizers, vibratory plate nebulizers, vibrating cone, and others. Vibrating mesh, vibrating cone or vibrating plate nebulizers are of particular interest as they do not require the use of an air compressor for dispensing, they have a minimum residual volume in the reservoir after dispensing a unit dose, and may be used to dispense low volumes of inhalable solutions. Exemplary membrane, mesh or vibrating plate nebulizers are described by R. Dhand (Respiratory Care, (December 2002), 47 (12), p. 1406-1418). Keller et al. (ATS 99th International Conference, Seattle, 16Q to 21Q 2003; poster 2727) describe the results of a study of AZTREONAM administration with a PARI eFlow nebulizer and report low oropharyngeal deposition, non-nebulized efficiency. -affected by total volume, a breathable fraction of 82 + 1.7%, constant dose administration by inhalation cycle time, and an excellent correlation between distributed dose, total volume and nebulization time, and high lung deposition expected.

The desired properties of a misting liquid generally include: 1) reduced viscosity; 2) sterile medium; 3) reduced surface tension; 4) stability in relation to the nebulizer mechanism; 5) moderate pH of about 4-10; 6) ability to form droplets with an MMAD of <5 μΓη or preferably <3 μιτι; 7) absence of irritating preservatives and stabilizers; 8) Proper tonicity. On the one hand, suspensions have some advantages, but on the other hand, solutions have other advantages.

Smaldone et al. (J. Aerosol Med. (1998), 11, 113-125) describe the results of a study on in vitro determination of inhaled mass and particle distribution of a budesonide suspension. They conclude that 2% -18% of the nebulizer budesonide load was distributed from the suspension, meaning that budesonide distribution was incomplete, resulting in a significant drug loss. In the thirteen most efficient systems, the suspension can be nebulized well enough for distribution to the lower respiratory tract.

Another study further demonstrated the highly variable nebulization efficiency from one nebulizer to another. Barry et al. (J. Allergy Clin. Immunol. (1998), 320-321) report that this variability should be taken into consideration when treating patients with nebulized budesonide. Berg et al. (J. Aerosol Sci. (1998), 19 (7), 1101-1104) also describe the highly variable nebulization efficiency of PULMICORT® suspension from one nebulizer to another. In addition, the mean aerodynamic mass diameter (MMAD) of nebulized droplets is highly variable from one nebulizer to the next. In general, suspensions are less efficiently nebulized than solutions, O1Riordan (Respiratory Care1 (2002), 1305-1313). Inhaled corticosteroids are used to treat asthma and are of significant benefit because they are delivered directly to the lungs' site of action. The purpose of an inhaled corticosteroid is to provide localized therapy with immediate drug activity in the lungs. Corticosteroids are well absorbed from the lungs. In fact, it can be assumed that all available drug at the receptor site in the lungs will be absorbed systemically. However, it is well known that using current methods and formulations, most of a dose of inhaled corticosteroid is swallowed and becomes available for oral absorption, resulting in unwanted systemic effects. For inhaled corticosteroids, high lung availability is more important than high oral bioavailability because the lung is the target organ. A product with high pulmonary availability has a greater potential to exert positive effects on the lung. Ideal inhaled corticosteroid formulation would provide minimal oral distribution, thereby reducing the likelihood of systemic adverse effects.

Most of the dose of corticosteroid delivered to the lung is absorbed and is available systemically. For the portion of the orally distributed inhaled corticosteroid dose, bioavailability depends on absorption from the G1 tract and the extent of the first passage metabolism in the liver. Since this oral corticosteroid drug delivery component provides no beneficial therapeutic effect, but may increase systemic side effects, it is desirable for the oral bioavailability of inhaled corticosteroid to be relatively low.

Both particle size and formulation influence the effectiveness of an inhaled corticosteroid. The formulation of a drug has a significant impact on the distribution of this drug to the lungs and therefore its effectiveness. Most important in drug delivery to the lung are the aerosol vehicle and the particle size distributed.

Additionally, a reduced degree of pulmonary deposition suggests a higher degree of oropharyngeal deposition. Due to a particular formulation employed, some corticosteroids are more likely to be deposited in the mouth and throat and may cause local adverse effects.

Although distribution to the receptor is the major determinant of bronchodilator efficacy, particle size appears to be more important in determining the efficacy of an inhaled corticosteroid. The lower airways have an internal perimeter of 2 micrometers (cm) or less. Thus, a particle inhaler having a mean air diameter of 1 mcm should have a greater breathable fraction than a particle inhaler having a mean diameter of 3.5 or 4 mcm. For patients with obstructive lung disease, all particles should ideally be no more than 2 to 3 mcm. A particle that is small (less than 5 mcm) is more likely to be inhaled into the lower airways of the lungs, thus improving efficacy. In contrast, particles larger than 5 mcm can be deposited in the mouth and throat, both reducing the proportion of particles that reach the lungs and potentially causing local adverse effects, such as oral candidiasis and hoarseness (dysphonia). Particles having a mean aerodynamic mass diameter (MMAD) of close to 1 mcm are considered to have a higher breathable fraction per dose than those with a diameter of 3.5 mcm or larger.

An additional disadvantage to nebulizing budesonide suspensions is the need to generate very small droplets, MMAD of about <3 μm. Since nebulized droplets are so small, then the micronized budesonide should be even smaller or in the range of 0.5-2.0 μm and the particles should have a narrow particle size distribution. The generation of such particles is difficult. Even so, efforts have been made to improve nebulization of budesonide suspensions with ultrasonic nebulizers by using submicron sized particles (Keller et al. In Respiratory Drug Delivery Vlll (2002), 197-206). A nanoparticle suspension (0.1-1.0 μηι) of the corticosteroid could be used to increase the proportion of breathable particles compared to a coarser suspension, as in the PULMICORT® suspension. No improvement was observed on the PULMICORT® suspension (budesonide particle size approximately 4.4 μηι in suspension). In addition, there are concerns regarding the use of nano-suspensions because small particles (<0.05 μιη) may induce an allergic response in a patient. Sheffield Pharmaceuticals, Inc. (St. Louis, MO; "The Pharmacokinetics of Nebulized Nanocrystal Budesonide Suspension in Health Volunteers", Kraft, and others in J. Clin. Pharmacol., (2004), 44: 67-72) described the preparation. and the evaluation of UDB (single dose budesonide), which is a suspension-based formulation containing budesonide nanoparticles dispersed in a liquid medium. This product is being developed by MAP Pharmaceuticals, Inc. (Mountain View, California). Seman and others (ATS 99th International Conference, Seattle, 16-21 May 2993; poster 2727) describe the results of a study evaluating the performance of the PARI eFlow nebulizer with a budesonide suspension (PULMICORT RESPULES, 500 pg). / ml, in a 2 ml ampoule) and report obtaining a MMAD of 3.6 to 4.2 μιτι and a respirable fraction greater than 67%.

Inhalation of drug particles as opposed to dissolved drugs is known to be disadvantageous. Brain et al. (Bronchial Asthma, 2- Ed. (Ed. EB Weis et al., Little Brown & Co. (1985), pp. 594-603) describe that the less soluble particles deposited on the cover. mucosa that covers the pulmonary airways and nasal passages are moved towards the pharynx by the cilia These particles would include the larger drug particles deposited in the upper respiratory tract, the mucus, the cells, and the fragments that come from the cavities. nasals and lungs meet in the pharynx, mix with saliva, and enter the gastrointestinal tract as they are swallowed In a mode described by this mechanism, particles are removed from the lungs with half-lives of minutes to Thus, there is little time for the solubilization of slowly dissolving drugs, such as budesonide.In contrast, the particles deposited in the non-ciliated compartments, such as the alveoli, have much longer residence times. Since it is difficult to generate very small budesonide particles for deep lung deposition, much of the inhaled suspension would probably be found in the upper respiratory tract than in the middle. However, it is much easier to generate small droplets from a solution than it is from a solids suspension. For these reasons, nebulization of a budesonide-containing solution should be preferred over that of a suspension.

O'Riordan (Respiratory Care (Nov. 2002), 47 (11), 1305-1313) reports that drugs may be delivered by nebulization of solutions or suspensions, but in general, nebulization of a solution is preferred. about that of a suspension. He reports that ultrasonic nebulizers should not be used in suspensions and should only be used in solutions.

O'Callaghan (Thorax, (1990), 45, 109-111), Storr et al. (Arch. Dis. Child (1986), 61, 270-273), and Webb et al. (Arch. Dis. Child (1986) , 61, 1108-1110) suggest that nebulization of corticosteroid solutions (in particular beclomethasone) may be preferred over that of suspensions because they may be inefficient if nebulized particles are too large to enter the lung in therapeutically amounts. effective. However, data presented by O'Callaghan (J. Pharm. Pharmacol. (2002), 54, 565-569) on solution nebulization against flunisolide suspension showed that the two act similarly. Therefore, it cannot be generalized that nebulization of a solution is preferred over that of a suspension.

Thus, there is a widely recognized need for a non-suspension formulation comprising a corticosteroid for administration via nebulization. However, the PULMICORT® suspension unit dose formulation is widely available and widely accepted in the field of inhalation therapy. It would be of great benefit to this field of therapy to provide a method of perfecting the administration of the PULMI-CORT® suspension unit dose formulation, or more generally, of a corticosteroid-containing suspension unit dose formulation.

However, the current focus on nebulizer therapy is to administer higher drug concentrations, use solution, preferably predominantly aqueous based solutions, rather than non-aqueous or non-aqueous alcoholic or alcoholic suspensions, if possible. minimize treatment time, synchronize nebulization with inhalation, and administer smaller droplets for deeper deposition of the drug into the lung.

Corticosteroid-containing solutions for nebulization are known. There are several different ways to prepare solutions for nebulization. These have generally been prepared by the addition of a co-solvent, surfactant, or buffer. However, co-solvents such as ethanol, polyethylene glycol and propylene glycol are only tolerated in low amounts when administered by inhalation due to respiratory tract irritation. There are limits to the acceptable levels of these co-solvents in inhaled products. Typically, co-solvents constitute less than about 35% by weight of the nebulized composition, although it is the total dose of co-solvent as well as its concentration that determines these limits. The limits are set by the propensity of these solvents to cause local irritation of the lung tissue, to form hypersommotic solutions that would draw fluid into the lungs, and / or to poison the patient. Furthermore, the most potential hydrophobic therapeutic agents are not sufficiently soluble in these co-solvent mixtures.

Saidi et al. (U.S. Patent No. 6,241,969) describe the preparation of corticosteroid-containing solutions for nasal and pulmonary delivery. Dissolved corticosteroids are present in an essentially non-aqueous concentrated form for storage or in a dilute aqueous base form for administration.

Keller et al. (In Respiratory Drug Delivery IX (2004) 221-231) describe the deposition of solution formulations containing budesonide and surfactants for children.

Lintz et al. (AAPS Annual Meeting and Exposition, Baltimore, November 8, 2004; Poster M1128) describe the preparation and aerosol characterization of liquid formulations containing budesonide, water, citrate salt, sodium chloride and alcohol, propylene glycol and / or surfactant such as Tween, Pluronic, or phospholipids with HLB values between 10 and 20. The aerosol characterization of such a combination surfactant solution in a membrane / vibrating mesh nebulizer (the Pari eFlow) in comparison A suspension was studied using adult and child breathing simulation. They reported a breathable fraction of 83.3% for PARI eFlow with solution and 61% for PULMICORT RESPULES with PARI LC +. They also reported the results considering respirable drug delivery rate (% drug <5 pm / min), dose delivered (% drug loaded to device), drug delivery rate (% drug / min) , and breathable dose (% <5 μιτι).

Schueepp et al. (ATS 99th International Conference, Seattle, May 16-21, 2003; Poster 1607) describe the determination of the performance of a customized Eflow Baby functional model with an experimental budesonide solution (100 mg at 0 , 5 ml) using a baby cast model and applying different breathing patterns.

An alternative method for administering the PULMICORT® suspension is the administration of a liposome formulation. Waldrep et al. (J. Aerosol Med. (1994), 7 (2), 135-145), in a reported mode, have been successful in preparing a budesonide liposome formulation and phosphatidylcholine derivatives.

None of the formulations identified above provided a method of perfecting the administration of a suspension-based unit dose formulation containing a corticosteroid. Rather, the general focus of the art has been completely on formulating a suspension, first preparing a liquid formulation, which is then divided into multiple unit doses that are put up for sale and then sold for use.

Solubilization of drugs by cyclodextrins and their derivatives is well known. Cyclodextrins are cyclic carbohydrates derived from starch. Unmodified cyclodextrins differ by the number of glycopyranose units linked together in the cylindrical structure. The source cyclodextrins contain 6, 7, or 8 glycopyranose units and are referred to as α-, β-, and γ-cyclodextrin, respectively. Each cyclodextrin subunit has secondary hydroxyl groups at positions 2 and 3 and a primary hydroxyl group at position 6. Cyclodextrins can be described as hollow truncated cones with hydrophilic outer surfaces and hydrophobic internal cavities. In aqueous solutions, these hydrophobic cavities provide an anchorage for hydrophobic organic compounds that can accommodate all or part of their structure in these cavities. This process, known as inclusion complex formation, can result in increased apparent aqueous solubility and stability for the drug in complex form. The complex is stabilized by hydrophobic interactions and does not involve the formation of any covalent bonds.

This dynamic and reversible equilibrium process can be described by Equations 1 and 2, where the amount in the complex form is a function of drug and cyclodextrin concentrations, and the equilibrium or binding constant, Kb. When cyclodextrin formulations are injected into the bloodstream, the complex rapidly dissociates due to the dilution and nonspecific binding effects of the drug on blood and tissue components.

<formula> formula see original document page 11 </formula> Equation 1

<formula> formula see original document page 11 </formula> Equation 2 The binding constants of cyclodextrin and an active agent can be determined by equilibrium solubility technique (T. Higuchi et al. in Advances in Analytical Chemistry and Instrumentation Vol. 4 "; CN Reilly ed.; John Wiley & Sons, Inc, 1965, pp. 117-212). Generally, the higher the concentration of cyclodextrin, the more the equilibrium process of Equations 1 and 2 is shifted to more complex formation, meaning that the concentration of free drug is generally decreased by increasing the concentration of cyclodextrin in solution. .

Cyclodextrins of non-derived origin are known to interact with human tissues and extract cholesterol and other membrane components, particularly with the accumulation in kidney tubule cells, resulting in toxic and sometimes fatal renal effects.

Originating cyclodextrins often exhibit a different affinity for any given substrate. For example, γ-cyclodextrin often forms complexes with limited solubility, resulting in Bs-type solubility curves. This behavior is known for a large number of steroids, which imposes serious limitations on the use of γ-CD in liquid preparations. . Β-CD, however, does not form a complex as well as a host of different classes of compounds. It has been shown for β-CD and γ-CD that derivation, for example, alkylation, not only results in better aqueous solubility of the derivatives compared to the source CD, but also alters the type of yield curves. Bs type limiting for the most linear type A curve (Bernd W. Müller and Ulrich Brauns1 "Change of Phase-Solubility Behavior by Gamma-Cyclodextrin Derivatization", Pharmaceutical Research (1985) pp. 309-310).

Chemical modification of the source cyclodextrins (usually hydroxyls) has resulted in improved safety derivatives while maintaining or enhancing the ability of complexes to form. Of the various derivative cyclodextrins prepared so far, only two appear to be commercially viable: 2-hydroxypropyl derivatives (HP-CD; neutral cyclodextrins being commercially developed by Janssen et al.), And sulfoalkyl ether derivatives, such as sulfobutyl ether, (SBE-CD; anionic cyclodextrins being developed by CyDex, Inc.). However, ΗΡ-β-CD still has toxicity that SBE-CD does not.

<formula> formula see original document page 13 </formula>

Sulfobutyl Ether-B-Cyclodextrin (Captisol®)

United States Patent Nos. 5,376,645 and No. 5,134,127 to Stella et al., U.S. Patent No. 3,426,011 to Parmerter et al., Lammers et al. (Red. Lock Chim. Pays-Bas (1972), 91 (6), 733-742); Stake (1971), 23 (5), 167-171) and Qu et al. (J. Inclusion Phenom. Macro. Chem., (2002), 43, 213-221) describe sulfoalkyl ether-derived cyclodextrins. References suggest that SAE-CD should be adequate to solubilize a wide range of different compounds. However, Stella describes that the molar ratio of sulfoalkyl ether-derived cyclodextrin to active ingredient suitable for solubilization of the active ingredient, even a corticosteroid, in water ranges from 10: 1 to 1:10.

A beta cyclodextrin sulfobutyl ether derivative (SBE-β-CD), in particular the derivative with an average of about 7 substituents per cyclodextrin molecule (SBE7-p-CD), is marketed by CyDex1 Inc. as CAPTISOL®. The anionic sulfobutyl ether substituent dramatically improves the aqueous solubility of the parent cyclodextrin. In addition, the presence of charges decreases the ability of the molecule to complex with cholesterol compared to the hydroxypropyl derivative. Non-covalent, reversible complexation of drug complexes with CAPTISOL® cyclodextrin generally allows for increased solubility and stability of drugs in aqueous solutions. Although CAPTI-SOL® is a relatively new but well-known cyclodextrin, its use in the preparation of nebulized corticosteroid-containing solutions has not been previously evaluated.

Hemolytic assays are generally used in the field of parenteral formulations to predict whether or not a particular formulation is likely to be inappropriate for injection into a patient's bloodstream. If the formulation being tested induces a significant amount of hemolysis, this formulation will generally be considered unsuitable for administration to a patient. Higher osmolality is generally expected to be associated with higher hemolytic potential. As depicted in FIG. 1 (Thompson, DO, Critical Reviews in Therapeutic Drug Carrier Systems, (1997), 14 (1), 1-104), the hemolytic behavior of CAPTISOL® is compared to that for the original β-cyclodextrin, hydroxypropyl derivatives ENCAPSIN® cyclodextrin (-3-4 substitution grade) and MOLE-CUSOL® cyclodextrin (-7-8 substitution grade), and two other sulfo-butyl ether derivatives, SBE1 -β-CD and SBE4-p-CD. Unlike other cyclodextrin derivatives, sulfoalkyl ether (SAE-CD) derivatives, in particular those such as CAPTISOL® (degree of substitution -7) and SBE4-p-CD (degree of substitution - 4), show essentially no hemolytic behavior and exhibit substantially less membrane damage potential than commercially available hydroxypropyl derivatives at the concentrations typically used to solubilize pharmaceutical formulations. The range of concentrations shown in the figure includes the concentrations typically used to solubilize pharmaceutical formulations when initially diluted in the bloodstream after injection. After oral administration, SAE-CD does not undergo significant systemic absorption.

The osmolality of a formulation is generally associated with its hemolytic potential: the higher the osmolality (or the more hypertonic), the greater the hemolytic potential. Zannou and others ("Osmotic properties of sulfobutyl ether and hydroxypropyl cyclodextrins", Pharma. Res. (2001), 18 (8), 1226-1231) compared the osmolality of solutions containing SBE-CD and HP-CD. As depicted in FIG. 2, SBE-CD containing solutions have a higher osmolality than HP-CD containing solutions, comprising similar concentrations of cyclodextrin derivative. Thus, it is surprising that SAE-CD exhibits lower hemolysis than does HP-CD at equivalent concentrations, although HP-CD has a lower osmolality.

Methylated cyclodextrins were prepared and their hemolytic effect on human erythrocytes was evaluated. These cyclodextrins have been found to cause moderate to severe hemolysis (Jodal et al., Proc. 4th Int. Symp. Cyclodextrins, (1988), 421-425; Yoshida et al., Int. J. Pharm., (1988), 46 (3)). , 217-222).

Administration of cyclodextrins to a mammal's lungs may not be acceptable. In fact, there is literature on the potential or observed toxicity of native cyclodextrins and cyclodextrin derivatives. The NTP Chemical Repository indicates that α-cyclodextrin may be harmful by inhalation. Nimbalkar et al. (Biotechnol. AppL Biochem. (2001), 33, 123-125) caution about the pulmonary use of a ΗΡ-β-CD / diacetildapsone complex due to its initial effect of retarding cell growth in the cell. lung.

Nevertheless, several studies regarding the use of cyclodextrins for inhalation have been described, although none have been marketed. Studies suggest that different drug-cyclodextrin combinations will be required for optimized or even useful specific inhaled or intranasal formulations. Attempts have been made to develop powders and solutions containing cyclodextrins for buccal, pulmonary and / or nasal distribution.

U.S. Patent No. 5,914,122 to Otterbeck et al. Describes the preparation of stable budesonide-containing solutions for nebulization. They demonstrate the use of cyclodextrin, such as β-CD, γ-CD or ΗΡ-β-CD, and / or EDTA as a stabilizer. Cyclodextrin is also suggested as a solubilizer for increasing budesonide concentration in solution. In each case, the longest shelf life they describe for any of their formulations is, in terms of acceptable retention of the active ingredient, only three to six months.

U.S. Pre-Deferred Patent Publication No. 20020055496 to McCoy et al. Describes essentially non-aqueous intraoral formulations containing β-β-CD. The formulations may be administered with an aerosol, spray pump or propellant.

Chuchalin Russian Patent No. 2180217 describes a stable solution containing budesonide for inhalation. The solution comprises budesonide, propylene glycol, poly (ethylene oxide), succinic acid, Trilon B, nipazole, thiourea, water, and optionally ΗΡ-β-CD.

Müller et al. (Proceed. Int'l. Symp. Control. King. Bioact. Mater. (1997), 24, 69-70) describe the results of a study on the preparation of budesonide microparticles by a dioxide process. supercritical carbon dioxide with Aerosol Solvent Extraction System (ASES) for use in a dry powder inhaler. ΗΡ-β-CD is suggested as a vehicle for a powder.

Müller et al. (U.S. Patent No. 6,407,079) describe pharmaceutical compositions containing β-β-CD. They suggest that nasal administration of a solution containing cyclodextrin is possible.

The art recognizes that it may be necessary to evaluate the structurally related variations of a particular type of cyclodextrin derivative to optimize the binding of a particular compound to this type of cyclodextrin derivative. However, it is often the case that there are no extreme differences in the binding of a particular compound with a first embodiment versus a second embodiment of a particular cyclodextrin derivative. For example, cases where extreme differences exist in the binding of a particular therapeutic agent to a first cyclodextrin derivative against a second structurally related cyclodextrin derivative. When such situations do exist, they are unexpected. Worth et al. (24h International Symposium on Controlled Releases of Bioactive Materials (1997)) describe the results of a study evaluating the utility of steroid / cyclodextrin complexes for pulmonary distribution. In side-by-side comparisons, β-CD, SBE7-p-CD, and ΗΡ-β-CD were evaluated for their ability to form inclusion complexes with beclomethasone dipropionate (BDP) and its active metabolite beclomethasone monopropionate (BMP). BMP was most easily solubilized with a cyclodextrin, and the observed order of solubilizing capacity was: ΗΡ-β-CD (highest)> β-CD> SBE7-β-CD. Thus, the technician would expect that SAE-CD derivatives would not be so suitable for use in solubilizing corticosteroids such as BMP or BDP. Although no results regarding actual utility in an inhaled formulation were described, they suggest that BMP, rather than BDP, would be a better alternative for developing a nebulizer solution.

Kinnarinen et al. (11lh International Cyclodextrin Symposium CD, (2002)) describe the results of an in vitro pulmonary deposition study of a budesonide / y-CD inclusion complex for dry powder inhalation. No advantage was observed by complex formation with γ-CD. Vozone et al. (11th International Cyclodextrin Symposium CD, (2002)) describe the results of a study on budesonide complex formation with γ-cyclodextrin for use in dry powder inhalation. No difference was observed within the emitted doses of the cyclodextrin complex or a physical mixture of budesonide and CD. However, a difference observed in the fine particle fraction of both formulations suggested that the use of a cyclodextrin complex for pulmonary drug delivery could increase the respirable fraction of the dry powder.

Pinto et al. (S.T.P. Pharma. Sciences (1999), 9 (3), 253-256) describe the results of a study on the use of ΗΡ-β-CD in an inhalable dry powder formulation for beclomethasone. ΗΡ-β-CD was evaluated as a complex or physical mixture with the drug in an in vitro deposition study of the dose emitted from a MICRO-HALER® inhalation device. The amount of respirable drug fraction was reportedly the highest with the complex and the lowest with the micronized drug alone.

Rajewski et al. (J. Pharm. Sci. (1996), 85 (11), 1142-1169) provide a review of the pharmaceutical applications of cyclodextrins. In this review, they cite studies evaluating the use of cyclodextrin complexes in dry powder inhalation systems.

Shao et al. (Eur. J. Pharm. Biopharm. (1994), 40, 283-288) described the efficacy of cyclodextrins as promoters of lung absorption. The relative efficacy of cyclodextrins in increasing pulmonary insulin absorption, as measured by pharmacodynamics, and the relative efficiency were rated as follows: dimethyl-p-cyclodextrin> α-cyclodextrin> β-cyclodextrin> γ-cyclodextrin> hydroxypropyl-p- cyclodextrin. In view of this report, the technician would expect that the water-soluble γ-CD derivative would be less suitable for delivering the compounds via inhalation than the respective β-CD derivative because the non-derivative β-CD is more suitable than the non-derived γ-CD.

Williams et al. (Eur. J. Pharm. Biopharm. (March 1999), 47 (2), 145-52) described the results of a study to determine the influence of the formulation technique for 2-hydroxypropyl beta -cyclodextrin (ΗΡ-β-CD) on aspirin stability in a suspension-based pressurized metered dose inhaler (pMDI) formulation containing a hydrofluoralkane (HFA) propellant. ΗΡ-β-CD was formulated into a pMDI as a lyophilized inclusion complex or a physical mixture with aspirin. Aspirin in the lyophilized inclusion complex exhibited the most significant degree of degradation during storage for 6 months, while aspirin alone in pMDI showed a moderate degree of degradation. Aspirin formulated in the physical mixture showed the lowest degree of degradation. In a manner described, ΗΡ-β-CD may be used to increase the stability of a chemically unstable drug, but the stability of the drug may be affected by the formulation preparation method.

Gudmundsdottir et al. (Pharmazie (Dec. 2001), 56 (12), 963-6) describe the results of a study in which midazolam was formulated in aqueous sulfobutyl ether-beta-cyclodextrin buffer solution. Nasal spray was tested on healthy volunteers and compared to intravenous midazolam in an open crossover trial. The nasal formulation, in a described manner, approximates intravenously in the rate of absorption, serum concentration and clinical sedation effect. No serious side effects were observed.

Srichana et al. (Respir. Med. (Jun. 2001), 95 (6), 513-9) report the results of a study to develop a new vehicle in dry powder aerosols. Two types of cyclodextrin were chosen; cyclodextrin (γ-CD) and dimethyl beta-cyclodextrin (DMCD) as carriers in dry powder formulations. Salbutamol was used as a model drug and a control formulation containing lactose and the drug was included. A dual stage collision apparatus (TSI) was used to evaluate the distribution efficiency of these dry powder formulations. From the results obtained, it was found that the formulation containing γ-CD increased drug distribution to the lower stage of IST (deposition = 65%) much more than that of both formulations containing DMCD (50%) and the control formulation (40%) (P <0.05). Red blood cell hemolysis with the DMCD complex was higher than that obtained with the γ-CD complex. Drug release in both γ-CD and DMCD-containing formulations was rapid (more than 70% were released within 5 min) and almost all of the drug was released within 30 min.

van der Kuy et al. (Eur. J. Clin. Pharmacol. (Nov. 1999), 55 (9), 677-80) describe the results of the pharmacokinetic properties of two intranasal dihydropyrgotamine mesylate (DHEM) containing formulation preparations. ) using a commercially available intranasal preparation. The formulations also contained randomly methylated β-cyclodextrin (RAMEB). No statistically significant difference in peak plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve (AUCO-8 h), Frel ( t = 8 h) and Cmax / AUC (t = 8 h) for the three intranasal preparations. The results indicate that the pharmacokinetic properties of intranasal preparations are not significantly different from commercially available nasal spray.

US Patents 5,942,251 and 5,756,483 to Merkus include pharmaceutical compositions for intranasal administration of dihydroergotamine, apomorphine and morphine, comprising one of these pharmacologically active ingredients in combination with a cyclodextrin and / or a disaccharide and / or a polysaccharide and / or a sugar alcohol.

U.S. Patent 5,955,454 describes a pharmaceutical preparation suitable for nasal administration containing a progestogen and a methylated β-cyclodextrin having a degree of substitution of between 0.5 and 3.0.

US 5,977,070 to Piazza et al. Discloses a pharmaceutical composition for the nasal delivery of compounds useful for treating osteoporosis, comprising an effective amount of a physiologically active truncated PTH or PTHrp analog or salt thereof, and an inhalant - absorption tensor selected from the group consisting of dimethyl-p-cyclodextrin.

US 6,436,902 to Backstrom et al. Describes compositions and methods for the pulmonary administration of a parathyroid hormone in the form of a dry powder suitable for inhalation, wherein at least 50% of the dry powder consists of in (a) particles having a diameter of up to 10 microns; or (b) agglomerates of such particles. A dry powder inhaler device contains a preparation consisting of a dry powder comprising

(i) a parathyroid hormone (PTH), and (ii) a substance that increases PTH absorption in the lower respiratory tract, where at least 50% of (i) and

(ii) consist of primary particles having a diameter of up to 10 microns, and where the substance is selected from the group consisting of a fatty acid salt, a bile salt or derivative thereof, a phospholipid, and a cyclodextrin or derivative of the same. U.S. Patent 6,518,239 to Kuo et al. Discloses a dispersible aerosol formulation comprising an active agent and a dipeptide or tripeptide for aerosol administration to the lung. Compositions in a described manner may also include polymeric excipients / additives, for example polyvinylpyrrolidones, derived celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropyl methylcellulose, Ficolls (a polymeric sugar), hydroxyethyl starch dextrates (e.g., cyclodextrins such as 2-hydroxypropyl-p-cyclodextrin and sulfobutyl ether-p-cyclodextrin), polyethylene glycols, and pectin.

Nakate et al. (Eur. J. Pharm. Biopharm. (Mar. 2003), 55 (2), 147-54) describe the results of a study to determine improved pulmonary absorption of cyclopeptide FK224 (low aqueous solubility) in rats by formulating it together with beta-cyclodextrin. The purpose of the study was to investigate the effect of pulmonary distribution on systemic absorption of FK224 compared to other routes of administration, and to determine the bioavailability (BA) of FK224 following pulmonary administration in rats using various dosage forms. . Following administration of an aqueous suspension, bioavailability was reduced to 2.7% compared with 16.8% for the solution. However, β-cycliodextrin (β-CD) has been found to be an effective additive in improving solubility of FK224. The bioavailability of the aqueous suspension containing β-CD was increased to 19.2%. Both C (max) and AUC of FK224 were observed to increase as the amount of β-CD increased. Plasma profiles showed constant absorption. They suggest that β-CD is an extremely effective additive in improving lung absorption of FK224. They also suggest that β-CD or derivatives with varying degrees of aqueous solubility are potential drug carriers for controlling pulmonary absorption.

Kobayashi et al. (Pharm. Res. (Jan. 1996), 13 (1), 80-3) describe the results of a study on the pulmonary distribution of dry salmon calcitonin (sCT) powders containing absorption enhancers. , in rats. Following intratracheal administration to rats of sCT dry powder and liquid preparations (solutions), plasma sCT levels and calcium levels were measured. In one described method, sCT in the dry powder and liquid was absorbed to almost the same degree. Absorption enhancers (oleic acid, lecithin, citric acid, taurocholic acid, dimethyl-β-cyclodextrin, octyl-β-D-glycoside) were much more effective in dry powder than in solution.

Adjei et al. (Pharm. Res. (Feb. 1992), 9 (2), 244-9) describe the results of a study on the bioavailability of leuprolide acetate following nasal distribution and inhalation to rats and healthy human beings. The systemic distribution of leuprolide acetate, a luteinizing hormone-releasing hormone (LHRH) agonist, was compared after inhalation (i.h.) and intranasal (i.n.) administration. The bioavailability of i.n. in rats was significantly increased by α-cyclodextrin (CD), EDTA, and solution volume. Absorption ranged from 8 to 46% compared to i.v controls. Studies in healthy men were conducted with leuprolide acetate i.n. by spray, or inhalation aerosol (i.h.), and subcutaneous (s.c.) and intravenous (i.v.) injection. The s.c. injection was 94% bioavailable compared to i.v. The bioavailability i.n. had an average of 2.4%, with significant variability from patient to patient. Inhalation distribution gave slightly lower variability among patients. The mean Cmax at a dose of 1 mg aerosol in solution was 0.97 ng / ml, compared with 4.4 and 11.4 ng / ml for suspended aerosols given at 1 and 2 mg cake dosages, respectively. . The average bioavailability of suspended aerosols (28% compared to s.c. administration) was four times higher than that of solution aerosol (6.6%).

CyDex (Cyclopedia (2002), 5 (1), 3) describes that SBE-CD is non-toxic to mice in an inhaled aerosol composition when present alone. They do not describe a nebulizable composition comprising a drug, in particular a corticosteroid, and SBE-CD. Studies comparing the nebulization of PULMICORT RESPULES and an inhalable aqueous solution of budesonide and SAE-CD in various nebulizers have been described (Zimmerer et al. Respiratory Drug Delivery IX (2004) 461 - 464). In deciding whether to administer a suspension against a solution, the type of nebulizer to be used should also be considered. The two most common types of nebulizers are the ultrasonic nebulizer and the air-powered jet nebulizer. There are significant differences between the two. For example, jet nebulizers cool rather than heat the liquid in the reservoir, while ultrasonic nebulizers heat the liquid. Although heating the solution in the reservoir may reduce the viscosity of the solution and increase droplet formation, overheating could result in drug degradation. The ultrasonic nebulizer is quieter and provides faster distribution than the jet nebulizer, but ultrasonic nebulizers are more expensive and are not advised to administer the steroid currently available for nebulization. More importantly, however, ultrasonic nebulizers generally provide a significantly higher rate of administration than jet nebulizers.

Asthma patients are often treated with short-acting or long-acting inhaled β2 agonists, inhaled anticholinergics, and inhaled corticosteroids alone, sequentially or in combination. Combinations of inhaled long-acting β2 agonists and corticosteroids are known, for example budesonide plus formoterol or fluticasone plus salmeterol are available in a dry powder inhaler. However, there is no example of such combinations being available as a nebulization solution. Combining the medications in one solution would reduce the time required to administer the medications separately.

For inhaled corticosteroids, lung availability is more important than high oral bioavailability because the lung is the target organ. A product with high pulmonary availability has greater potential for positive lung effects. ICS idela would have minimal oral bioavailability, reducing the likelihood of systemic adverse effects.

Although extremely effective in treating asthma, inhaled corticosteroids can have several adverse side effects such as oral thrush, hoarseness (dysphonia), and pharyngitis. Therefore, inhaled corticosteroids are best distributed by a method that minimizes oral and / or pharyngeal deposition of corticosteroids and instead maximizes pulmonary distribution.

Some corticosteroids have a hydroxyl group at position 21 of the corticosteroid. Those compounds include budesonide, flunisolide, triamcinolone acetonide, beclomethasone monopropionate, and the active form of ciclesonide (desisoburityl-ciclesonide). It is known that ciclesonide is inhaled as an inactive compound and converted by esterases into the lung to its active form desisobutyryl ciclesonide (des-CIC). Budesonide conjugates to form highly lipophilic intracellular fatty acid esters. Budesonide forms conjugates with 5 fatty acids: oleate, palmitate, linoleate, palmitoleate, and arachidonate.

In summary, the technical technique suggests that in some cases nebulization of solutions may be preferred over that of suspensions and that in some cases an ultrasonic nebulizer, vibration mesh, electronic mechanism or other aerosolization mechanism. may be preferred over an air-powered jet nebulizer, depending on the liquid nebulization formulations being compared. Although the technique describes formulations of inhaled solutions containing a corticosteroid and cyclodextrin, the results of the technique are not predictable. In other words, the combination of one cyclodextrin with one drug does not suggest that another cyclodextrin may be adequate. Nor does the technique suggest that an inhalable cyclodextrin-corticosteroid formulation will have advantages over another inhalable cyclodextrin-corticosteroid formulation.

There remains a need in the art for an inhalable formulation containing budesonide in stabilized aqueous solution which does not require the addition of preservatives and which provides significant advantages over other inhalable formulations containing budesonide in aqueous solution. There also remains a need for a method of perfecting the administration of nebulised bude- deside-containing suspension formulations by converting the suspension into a solution.

There is also a need to develop improved systems that can solubilize water-insoluble drugs for nebulization, and minimize the co-solvent levels required to accomplish this. The ideal system would consist of non-toxic ingredients and would be stable for long periods of storage at room temperature. When nebulized, it would produce breathable droplets of less than 10 microns or less than 5 microns or less than 3 microns and a substantial portion of extra-fine aerosol in the size range of less than about 1 micron.

There remains a need for a method of improving the nebulised administration of a suspension-based unit dose formulation. Such a method would reduce the overall administration time, increase the overall amount of drug administered, reduce the amount of drug left in the nebulizer reservoir, increase the portion of lung deposition relative to oropharyngeal corticosteroid deposition, and / or would increase deep penetration of the corticosteroid into the lung compared to such non-perfecting administration of the suspension-based unit dose formulation.

Summary of the Invention

The present invention seeks to overcome the disadvantages of known formulations. As such, an inhalable formulation based on cyclodextrin derived, for example, based on sulfoalkyl ether cyclodextrin (SAE-CD) is provided. The present formulation includes a corticosteroid as an active agent. The present formulation may provide increased solubility and / or increased chemical, thermochemical, hydrolytic and / or photochemical stability of the active agent or other ingredients in the formulation. In addition, the present formulation may have other advantages, for example, increased drug delivery, increased drug delivery rate, reduced treatment time, reduced toxicity, ease of manufacture, certainty of sterility, improved stability, bioabsorption. no particle size control requirement, increased exit rate, increased total output, no problem with solid particle development, and / or no need to confirm the formation of a suspension over other inhalable formulations in solution or suspension containing a corticosteroid such as budesonide.

The invention provides a formulation, system and method for treating a respiratory disease or disorder that is therapeutically responsive to corticosteroid therapy. The system of the invention comprises a nebulizer, and a liquid formulation of the invention. The liquid formulation of the invention comprises a corticosteroid dose, an aqueous liquid carrier and a solubility enhancer.

The invention provides a method of treating, preventing or ameliorating in a patient a corticosteroid responsive disease or disorder, meaning a disease or disorder in a patient that can be treated with a therapeutically effective amount of corticosteroid to provide a clinical or therapeutic benefit. to the patient. The method comprises: providing an aqueous inhalable formulation comprising a corticosteroid, an aqueous liquid carrier, and solubility enhancer; and delivering or administering by drinking to a patient in need thereof a dose of at least about 25 pm, 40 pm, at least 45 pm, at least 48 pm, 45 - 1000 pm, about 1 pm to 20 mg, or 1 pm at 10 mg, 0.01 mg at 10 mg, 0.025 mg at 10 mg, 0.05 mg at 5 mg, 0.1 mg at 5 mg, 0.125 mg at 2 mg, 0.25 mg 2 mg, 0.5 mg to 2 mg, 1 pg, 10 pg, 25 pg, 50 pg, 100 pg, 125 pg, 200 pg, 250 pg, 25 to 66 pg, 48 to 81 pg, 73 to 125 pg , 40 pg, 64 pg, 95 pg, 35 to 95 pg, 25 to 125 pg, 60 to 170 pg, 110 pg, 170 pg, 45 to 220 pg, 45 to 85 pg, 48 to 82 pg, 85 to 160 pg , 140 to 220 pg, 120 to 325 pg, 205 pg, 320 pg, 325 pg, 90 to 400 pg, 95 to 170 pg, 165 to 275 pg, or 275 to 400 pg of corticosteroid. In some embodiments, the corticosteroid is budesonide.

In some embodiments: 1) the inhalable formulation has a volume of about 10 pl to 100 ml, 50 pl to 50 ml, 50 pl to 10 ml, 0.1 to 10 ml, 0.1 ml less than 10 ml, 0.1 ml to 7.5 ml, 0.1 ml to 5 ml, 0.1 ml to 3 ml, 0.1 ml to 2 ml, 0.1 ml to 1 ml, 0.05 ml to 7.5 ml, 0.05 ml to 5 ml, 0.05 ml to 3 ml, 0.05 ml to 2 ml, or 0.05 to 1 ml; 2) the dispensing or administration step is conducted for a period of less than 30 minutes, less than 20 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, less than 3 minutes, or less than 2 minutes, or the time is around 0.05 to 10 minutes, about 0.1 to 5 minutes, about 0.1 to 3 minutes, about 0.1 to 2 minutes, about 0 1 to 1.5 minutes, about 0.5 to about 1.5 minutes, or about 1 minute, or the time is around the time taken for a patient to perform a single breath (about 1 to 3 or 1 to 5 seconds); 3) 20% to 85%, or 30% to 80%, or at least 30%, at least 40%, at least 56%, at least 59%, at least 62% of the corticosteroid dose is distributed to patient's lungs; 4) the formulation, system or method provides an enhanced pharmacokinetic profile of 1.5 to 8 times, 1.5 to 6 times, 1.5 to 4 times, 1.5 to 2 times, 1.64 to 3, 55 times for Cmax, 1.48 to 6.25 times for Cmax, 1.59 to 3.55 or 1.19 to 6.11 times for AUCinf1 1.69 - 3.67 or 1.21 to 7.66 times for AUCiast, at a standard dose, as compared to administering a suspension formulation comprising approximately the same amount of corticosteroid and delivered substantially under the same conditions; 5) No more than 15% to 85%, 15% to 70%, no more than 20% to 70%, no more than 50%, no more than 40%, or no more than 60% corticosteroid doses are distributed to the patient outside the lung.

The present inventors have unexpectedly found that SAE-CD is systemically absorbed following administration via inhalation. It is also eliminated from the lungs. SAE-CD also forms complexes with corticosteroids in aqueous inhalable liquid formulations. Co-administration of corticosteroids with SAE-CD may result in increased exit rate and total drug delivery compared to a control that excludes SAE-CD. In addition, an inhalable solution administered by nebulization provides other advantages mentioned herein compared to a control / reference sample of a suspension comprising substantially the same amount of corticosteroid in substantially the same volume of liquid when administered under substantially the same. conditions.

An inhalable solution may be used in most types of nebulizers as suspensions clog vibrating mesh nebulizers and do not work well in ultrasonic nebulizers. Nebulizers would be more easily cleaned from residual corticosteroids resulting in less contamination. When a drug in solution will be evenly distributed in large and small droplets leaving the nebulizer, the fine particle fraction will contain more corticosteroids resulting in a larger breathable dose than can reach the peripheral lung and smaller airway. This can result in less total drug deposition in the oropharyngeal cavity and being swallowed, thereby reducing the potential for unwanted side effects while enhancing bioavailability and maximizing the desired effect. The inhalable solution will also reduce the amount of drug at the unit dose and / or reduce the time to achieve the desired amount of drug in the lung. The inhalable solution is more easily manufactured and loaded in unit doses and product performance does not depend on very tight control of the included corticosteroid particle size and maintenance of a homogeneous suspension during loading. However, such a smaller particle size will generally facilitate faster dissolution during manufacturing. It is not necessary to maintain strict control as described above. It can be terminally sterilized without risk of changing the suspended corticosteroid corticosteroid particle size. The inhalable solution is not subjected to change due to particle growth through Ostwald ripening or agglomeration, so the amount of drug in the respirable fraction will not change over prolonged time. It does not need to be resuspended prior to administration with carefully prescribed procedures to reduce foaming so as not to create large dose variation. It can be more accurately diluted to obtain the desired amount of drug in the volume placed in the nebulizer. Alternatively, dose adjustment can be controlled more easily by adjusting the nebulization time when the concentration of the inhalable solution does not change as rapidly in the nebulizer as it does the suspension concentration, especially in air jet nebulizers. .

A SAE-CD containing formulation may be prepared with sufficient solubility and stability of the active agent for a commercial product. If necessary, the SAE-CD containing formulation may be prepared as a clear aqueous solution which may be sterile filtered through a filter having a pore size of 0.45 μηι or less and which is stable and stored under a variety of storage conditions. The invention thus provides a filter sterile liquid formulation comprising a solution of the invention and a method of sterilizing a solution of the invention by sterile filtration through a filter. Sterile filtration can be done without substantial mass loss of solubilized corticosteroids, meaning less than 5% mass loss.

Any corticosteroid suitable for administration by inhalation may be used in accordance with the invention. Exemplary suitable corticosteroids are listed here. Some embodiments of the invention comprise a corticosteroid having a lipophilicity approaching or exceeding that of flunisolid. Some inventive modalities exclude a corticosteroid having lower lipophilicity than flunisolid, that is, modalities excluding hydrocortisone, prednisolone, prednisone, dexamethasone, betamethasone, methylprednisolone, triamcinolone, flu- cortolone.

Another aspect of the invention provides a liquid formulation comprising an effective amount of corticosteroid, such as bude-sonide, and a SAE-CD, wherein SAE-CD is present in an amount sufficient to dissolve and stabilize the corticosteroid during storage. - nage.

Another aspect of the invention provides a method of enhancing the administration of corticosteroids to a patient by nebulization, the method comprising the steps of: providing in a unit dose an aqueous suspension formulation comprising water and corticosteroids suspended therein;

combining the suspension with sufficient SAE-CD to, and for a time sufficient to solubilize the corticosteroid and form a solution; and

administering the solution to the patient, wherein the amount of time required to administer a therapeutic dose of corticosteroid with the solution is less than the amount of time required to administer the same therapeutic dose of corticosteroid with the suspension under similar nebulization conditions. , or otherwise comparable.

When administered with a nebulizer, a nebulization suspension will provide a first corticosteroid output rate under a first group of nebulization conditions. However, when SAE-CD is added to the suspension and mixed with it, a sufficient amount of corticosteroid is dissolved to form a liquid nebulization formulation, which provides a higher corticosteroid output rate compared to formulation excluding SAE-CD when administered under substantially the same conditions. In one embodiment, the drug exit rate of the formulation is increased over that of the suspension, although the total volume of nebulized composition, that is, the total volume of solution emitted by the nebulizer, has not increased. In another embodiment, SAE-CD is present in an amount sufficient to solubilize at least 50%, at least 75%, at least 90%, at least 95% or substantially the entire corticosteroid.

In some embodiments, SAE-CD is present in an amount sufficient to decrease the amount of non-solubilized corticosteroid in the suspension formulation and to enhance nebulized administration of the suspension formulation. In yet another embodiment, SAE-CD is present in an amount sufficient to solubilize sufficient corticosteroids such that the suspension formulation to which SAE-CD has been added is converted into a solution, a substantially clear solution ( containing less than 5% precipitated solid), or a clear solution. It is possible that the other components of the suspension formulation may not dissolve completely in or may separate from the SAE-CD containing solution formulation.

According to another embodiment, a nebulizer charged with a corticosteroid / SAE-CD-containing solution generates smaller droplets than does the same nebulizer charged with a corticosteroid / HP-p-CD-containing solution, operated under otherwise conditions. similar. As a result of generating smaller droplets, the SAE-CD comprising system is enhanced over an otherwise similar system comprising ΗΡ-β-CD, as the SAE-CD based system will generate a larger proportion of droplets. breathable and allow deeper penetration into the lung.

Some aspects of the invention provide the use of SAE-CD in a nebulizable unit dose liquid formulation. In one embodiment, the invention provides the use of SAE-CD to convert a sterilizable suspension-based unit dose-containing formulation that can be nebulized to a nebulizable corticosteroid-containing liquid unit dose formulation.

Some specific embodiments of the invention include those where: 1) the molar ratio of budesonide to SAE-CD is from 0.5 to 0.0001 (1: 2 to 1: 10,000), 1: 1 to 1: 100, 1: 1 at 1: 10,000, or 0.1 (1:10) to 0.03 (1: 33.33). The molar ratio of SAE-CD to corticosteroid in forrriaulation or system is generally greater than 10: 1, greater than about 11: 1, greater than 13: 1, or greater than 14: 1. Depending on the corticosteroid used in the formulation, the molar ratio of corticosteroid to SAE-CD may vary to obtain a solution suitable for inhalation administration for the treatment of a respiratory disease or disorder. In some embodiments, the nebulization composition comprises at least 4.8 ± 0.5 wt% / vol. SAE-CD to provide a self-preserving formulation for a predetermined period of time. In some embodiments, the nebulization composition comprises less than or about 21.5 ± 2 wt% SAE-CD. In some embodiments, SAE-CD is present in an amount sufficient to provide a clear solution. For example, the nebulizing composition may be visibly clear as observed by the eye without assistance.

Some suitable SAE-CD's include, for example, 4-p-CD sulfobutyl ether or 7-p-CD sulfobutyl ether, θ-γ-CD sulfobutyl ether, 3 to δ-γ-CD sulfobutyl ether, or a sulfobutyl ether 5-γ-CD, or a compound of formula 1 or a mixture thereof.

A composition of the invention may also comprise a conventional preservative, an antioxidant, a buffering agent, an acidifying agent, a solubilizing agent, a complexing enhancing agent, saline, an electrolyte, another therapeutic agent, a alkalizing agent. , a tonicity modifier, surface tension modifier, viscosity modifier, surfactant, density modifier, volatility modifier, or a combination thereof. If desired, the composition also comprises a liquid carrier except water. If a conventional preservative is included in the composition, the corticosteroid, such as bude-sonide, may have a greater binding to SAE-CD than a conventional preservative. A composition may be purged with an inert gas prior to storage to substantially remove all oxygen contained in the formulation. In general, the formulation or composition of the invention has a shelf life of at least 6 months depending on the intended use.

The formulation may be prepared at a temperature of or above 5 ° C, at or above 25 ° C, at or above 35 ° C, at or above 450 ° C or at or above 50 ° C. Specific embodiments of the methods of preparing a liquid formulation include those wherein: 1) the method additionally comprises the step of sterile filtering the formulation through a filter medium having a pore size of 0.1 microns or larger; 2) the liquid formulation is sterilized by irradiation or autoclaving; 3) the nebulization solution is purged with nitrogen or argon or another pharmaceutically acceptable inert gas prior to storage such that a substantial portion of the oxygen dissolved in and / or in contact with the surface with the solution is removed.

The invention provides a method of stabilizing corticosteroids in an aqueous corticosteroid-containing formulation comprising the step of adding SAE-CD to a corticosteroid-containing aqueous suspension or solution formulation in an amount sufficient to reduce the rate. of corticosteroid degradation compared to a control sample excluding SAE-CD.

The invention also provides a method of improving the administration of a nebulized aqueous inhaled corticosteroid-containing suspension unit dose formulation, the method comprising the step of adding SAE-CD to a suspene unit dose formulation. - are aqueous corticosteroid-containing in an amount sufficient to solubilize the corticosteroid to form a unit dose formulation of an inhalable aqueous corticosteroid-containing solution, the enhancement comprising increasing the output rate and / or the proportion of nebulized corticosteroid.

The invention provides a method of reducing the amount of time required to provide a therapeutically effective amount of corticosteroid to a patient by inhaling a corticosteroid-containing composition with a nebulizer, the method comprising the steps of: including SAE-CD in the composition in question. an amount sufficient to solubilize the corticosteroid to form a solution containing inhalable aqueous corticosteroid; and administering the solution to the patient by inhalation with a nebuliser, wherein the amount of time required to provide a therapeutically effective amount of corticosteroid to the patient with the solution is reduced compared to the amount of time required to provide a therapeutically effective amount of corticosteroid to the patient. patient with a corticosteroid-containing suspension comprising the same amount or concentration of corticosteroids, when the suspension and solution are administered under otherwise similar nebulization conditions. In some embodiments, the time required to administer or release a corticosteroid dose is less than 30 minutes, less than 20 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, less than 3 minutes, or less than 2 minutes, or the time is about 0.05 to 10 minutes, about 0.1 to 5 minutes, about 0.1 to 3 minutes, about 0.1 to 2 minutes, about 0.1 to 1.5 minutes, about 0.5 minutes to about 1.5 minutes, or about 1 minute, or around the time it takes for a patient to perform a single breath (about 1 to 3 seconds, or 1 to 5 seconds). Time will vary according to the corticosteroid dose at the corticosteroid concentration in, and the volume of inhalable composition in a nebulizer reservoir, and will also depend on the nebulizer shape, nebulization efficiency, and reservoir volume. In a given nebulizer, the smaller the volume of the inhalable composition, the faster a corresponding dose of corticosteroid is nebulized. The higher the corticosteroid concentration in an inhalable composition, the faster a corticosteroid dose can be administered or distributed.

The exit rate (the rate at which the corticosteroid dose is delivered or delivered) will vary according to the nebulizer performance parameters used to administer it. The higher the exit rate of a given nebulizer, the shorter the time required to dispense or administer an inhalable composition as defined herein or corticosteroid dose.

The invention also provides an inhalable composition comprising a water soluble γ-CD derivative, a corticosteroid (esterified or non-esterified) and an aqueous liquid medium. Another embodiment of the invention also provides an inhalable composition comprising a water-soluble β-CD derivative, a (non-esterified) corticosteroid and an aqueous liquid medium.

In addition, the invention provides an improved system for administering an inhaled formulation containing inhaled corticosteroids, the improvement comprising including SAE-CD in the inhalable formulation such that SAE-CD is present in a sufficient amount. to provide an increased rate of inhaled corticosteroid compared to administration of an inhalable control formulation excluding SAE-CD1 but otherwise being administered under approximately the same conditions.

The invention may be used to provide a system for administering a corticosteroid by inhalation, the system comprising an inhalation device, such as a nebulizer, and a drug composition comprising a therapeutically effective amount of corticosteroid, liquid carrier and SAE. -CD present in an amount sufficient to solubilize corticosteroids when exposed to an aqueous environment, where the molar ratio of corticosteroids to SAE-CD is in the range of about 0.072 (1: 13.89 or 1:14) to 0 .0001 (1: 10,000) or 0.063 (1: 15.873 or about 1:16) to 0.003 (1: 333.33 or about 1: 333). The molar ratio of SAE-CD to corticosteroid ranges from> 10: 1 to about 1000: 1, about> 10: 1 to about 100: 1, from> 10: 1 to about 50: 1, from> 10 : 1 to about 30: 1, from> 10: 1 to about 500: 1. During operation, the system forms droplets having an MMAD in the range of about 1-8 μ or 3-8 μ. The corticosteroid is distributed at a rate of at least about 20-50 μς / ηιίη, where this range may increase or decrease according to the concentration of corticosteroid in the nebulizer solution in the nebulizer reservoir.

As a result of using SAE-CD corticosteroid therapy with an inhalable nebulization solution, one can expect advantages such as increased drug delivery, increased distribution, especially to the peripheral or lower airways, facilitated by aerosol. produced, potentially improved treatment of asymptomatic, nocturnal asthma, and recovery from acute asthma attacks, increased drug administration rate, reduced treatment time, improved formulation stability, and / or improved patient compliance compared to corticosteroid therapy comparable to an inhaled nebulizer suspension or pressurized metered dose inhaler (pMDI), chlorofluorocarbon (CFC) or hydrofluoralkane (HFA) suspension.

The invention may be employed in a kit comprising SAE-CD, an aqueous vehicle, and corticosteroid, wherein the kit is adapted for the preparation of a nebulization solution. Kit modalities are detailed below. The invention provides the potential to accommodate combination products for overcoming incompatibilities with suspension by other dosage forms in solution.

The formulation and liquid composition of the invention provides enhanced corticosteroid bioavailability / bioabsorption compared to an aqueous suspension based formulation containing approximately the same amount of corticosteroid and excluding SAE-CD. The liquid formulation or composition provides a higher ratio of AUCi (or AUCt) to the amount of budesonide released to a patient than the suspension-based formulation provides. Of this mold, the liquid formulation and / or composition provides a clinical benefit or improved therapeutic benefit over the suspension based formulation.

The invention also provides a method of administering a corticosteroid to a patient comprising the step of administering by inhalation to a patient an aqueous liquid composition comprising a unit dose of corticosteroid dissolved therein, wherein the composition provides an AUCt. average, normalized for corticosteroid dose, of at least 6 (pg * h / ml) per pg of corticosteroids administered. In some embodiments, the unit dose comprises at least 45 pg, at least 48 pg, 45-1000 pg, about 1 pg to 20 mg, about 1 pg to 10 mg, 0.01 mg to 10 mg, 0.025 mg 10 mg, 0.05 mg 5 mg, 0.1 mg 5 mg, 0.125 mg 5 mg, 0.25 mg 5 mg, 0.5 mg 5 mg, 0.05 mg 2 mg , 0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg, 1 pg, 10 pg, 25 pg, 50 pg, 100 pg, 125 pg, 200 250 pg, 25 to 66 pg, 48 to 81 pg, 73 to 125 pg, 40 pg, 64 pg, 95 pg, 35 to 95 pg, 25 to 125 pg, 60 to 170 pg, 110 pg, 170 pg, 45 to 220 pg, 45 to 85 pg, 48 to 82 pg, 85 to 160 pg, 140 to 220 pg, 120 to 325 pg, 205 pg, 320 pg, 325 pg, 90 to 400 pg, 95 to 170 pg, 165 at 275 pg, or 275 to 400 pg corticosteroid. In some embodiments, normalized AUCt is dose-based for the patient, normalized AUCt is based on the patient's lung dose, or normalized AUCt is based on the delivered dose or nominal dose. As used herein, AUCt (or AUCiast, AUCo-t) is the area under the plasma level versus the time curve for the last time point for which a quantifiable value exists.

The invention also provides a method of administering a corticosteroid to a patient comprising the step of administering by inhalation to a patient a liquid composition comprising a unit dose of corticosteroid dissolved therein, wherein the composition provides an average AUCi, normalized to the corticosteroid dose of at least 8 (pg * h / ml) per pg corticosteroid administered. In some embodiments, the unit dose comprises at least 45 pg, at least 48 pg, or 45 - 1000 pg, about 1 μg to 20 mg, about 1 pg to 10 mg, 0.01 mg to 10 mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125 mg to 5 mg, 0.25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, or 0.5 mg to 2 mg corticosteroid. In some embodiments, normalized AUCi is dose-based for the patient, normalized AUCi is dose-based for the patient, or normalized AUCi is based on delivered dose or nominal dose. As used herein, AUCi (AUCjnf, AUC (C) -H is AUC extrapolated to infinity.

When the aqueous liquid solution formulation of the invention is administered by inhalation it may provide at least a two-fold increase in AUCt or AUCi, normalized to corticosteroid dose, per microgram of corticosteroid administered as compared to administration. by inhalation of an aqueous liquid suspension formulation comprising substantially the same amount of corticosteroid suspended therein. In some embodiments, the formulation provides at least a 1.6 to five fold increase (range as determined on an individual patient basis or an average of 3 with a standard deviation of +/- 1 as determined from patient data individual) or a two to fourfold increase (as determined using the geometric mean across a patient population) in AUCt or AUCi, normalized to corticosteroid dose, per microgram of corticosteroid administered. The basis for the amount of "corticosteroid administered" may be "patient dose" or "lung dose" or "emitted dose" or "nominal dose" or "nominal available dose" or "loaded dose".

The aqueous liquid formulation may be administered with any type of device available for delivery of a liquid lung formulation. For example, the formulation may be administered with an ultrasonic, capillary, electromagnetic, air-driven jet nebulizer, pulsatile membrane, pulsatile plate (disc), pulsatile mesh, a nebulizer comprising a vibration generator and an aqueous chamber, and a nebulizer comprising a nozzle arrangement.

In some embodiments, the invention provides a system comprising a nebulizer and an aqueous liquid formulation / composition as described. When loaded with a liquid formulation of the invention comprising a corticosteroid dose, the nebulizer may provide an increasing corticosteroid concentration decrease (RIC) rate in the formulation in the nebulizer reservoir, in particular when comparing the performance of the liquid formulation to the corticosteroid. performance of a suspension-based formulation, eg PULMICORT RESPULSES, in the nebuliser. In some modalities, the percentage decrease in the ICN ranges from 10% to 60%, 15% to 60%, 20% to 60%, 30% to 60%, or 40% to 60%. In some embodiments, the system may provide an ICN of 0 to 40, 1 to 40, 5 to 30, or 10 to 30 mcg corticosteroid / mL solution volume per minute of operation / nebulization.

The pharmacokinetic enhancement provided by the system and formulation / composition of the invention can be determined by comparing Cmax, AUC and Tmax parameters. In some embodiments, the formulation and system of the invention may provide a C max (pg corticosteroid / ml) of 90 to 900, 200 to 600, 200 to 550, 200 to 250, 400 to 450, 500 to 600, 225, 437, or 545 on a non-standard dose basis. The formulation and system of the invention may provide a standard dose C max (pg / ml / pg) of: 1) 0.3 to 2, 0.35 to 2, 0.6 to 1.5, 0.5 to 1, 2, 0.8 to 1, 0.8 to 0.9, 0.7 to 0.8, 0.4, 1.9, 0.6, 1.5, 0.5, 1.2, 0, 35, 2, 0.7, 0.8, or 0.9 on a standard basis of nominal available dose; 2) 3.4 to 9.2, 3.5 to 8.5, 5.5 to 9.2, 4.5 to 7.5, 5.8 to 7, 3.4, 3.5, 4.5, 5.5, 9.2, 8.5, 7.5, 5.8, 5.9, 6, or 7 on a normal donor-to-lung basis; 3) 1.7 to 7.5, 3.2 to 4.1, 1.9 to 6, 3.2 to 7.5, 1.7 to 5.2, 3.6, 4.1, 3, 2, 1.9, 6, 3.2, 7.4, 7.5, 1.7, 5.2 or 5.3 on a normalized dose basis for the patient; 4) 0.9 to 3, 1.7 to 2.2, 0.9 to 3, 1 to 3, 1.7 to 3.3, 1 to 2.7, 1.9, 2.1, 2.2, 1.7, 0.9, 1, 2, 3, 2.9, 3.2, 3.3, or 2.7 on a normal emitted dose basis.

In some embodiments, based on the non-normalized corticosteroid dose, the Cmax provided by the corticosteroid solution is 1.6 to 2, 1.5 to 3, 1.5 to 2.5, 1.5 to 2, 1 , 5, 1.6, 2, 2.5, or 3 times higher than the Cmax provided by the suspension-based formulation when the dose of corticosteroid in solution and suspension is approximately the same amount charged. Based on normalization to the nominal available corticosteroid dose, the Cmax provided by the corticosteroid solution is 1.8 to 6.2, 1.5 to 6.5, 2 to 6.5, 1.5 to 5.5 , 2 to 4, 1.5 to 4, 1.5 to 3, 2.7, 3.3, 3.4, 1.5, 6.5, 2, 5.5, 4, or 3 times the Cmax provided by the suspension-based formulation. Based on normalization for the corticosteroid dose to the lung, the Cmax provided by the corticosteroid solution is 1.4 to 4.3, 1.4 to 4.5, 1.5 to 4.5, 1, 5 to 3.5, 1.5 to 3, 1.4 to 3, 1.5 to 2.5, 1.5 to 2, 2, 2.3, 1.4, 4.5, 3.5, 3, 1.5 or 2.5 times higher than the Cmax provided by the suspension-based formulation. Based on normalization for the patient's corticosteroid dose, the Cmax provided by the corticosteroid solution is 2 to 3.5, 2 to 5, 1.7 to 3.8, 1.7 to 5, 2, 7, 3, 2.4, 2, 3.5, 5, 1.7, or 3.8 times higher than the Cmax provided by the suspension based formulation. Based on normalization for the emitted corticosteroid dose, the Cmax provided by the corticosteroid solution is 1.9 to 6.3, 1.75 to 6.5, 2.2 to 4.2, 2.2 to 6.3, 1.9 to 4.2, 3.2, 3.5, 3.6, 2.8, 1.75, 6.5, 2.2, 4.2, or 6.3 times higher than the Cmax provided by the suspension based formulation.

In some embodiments, the Cmax provided by the corticosteroid solution is at least 1.5, 1.6, 2, 2.6, and 3 times higher than the Cmax provided by the suspension-based formulation when the corticosteroid dose in solution is about 2 times lower than the suspension dose.

In some embodiments, the formulation and system of the invention may provide an AUCinf (pg * h / ml) of 500 to 1700, 530 to 1650, 250 to 2500, 280 to 1300, 780 to 1300, 980 to 2450, 275, 775, 980, 2400, 2500, 1300, 1290, 530, 1650, 250, 280 or 780 on a non-standard dose basis. The formulation and system of the invention may provide a normalized dose (pg / ml / pg) AUCint of: 1) 1 to 5.5, 2 to 2.2, 1 to 5.3, 1.1 to 5.2, 1.5 to 2.6, 1.3 to 3.3, 2, 2.1, 2.2, 1, 5.5, 5.3, 5.2, 1.5, 2.6, 1.3 or 3.3 in a standard base of nominal available dose; 2) 10 to 25, 14 to 18, 10.2 to 20, 13.6 to 18.8, 11.2 to 24.7, 10.2, 20, 13.6, 14, 19, 18.8, 11, 11.2, 25, 24.7, 14.2, 16.2, 17.3 on a normalized dose basis for the lung; 3) 4 to 16, 4.2 to 16.1, 8 to 12.2, 5.4 to 16, 5.4 to 17, 8.5 to 9.6, 8.5, 9.5.9, 6, 4.2, 16.1.8, 12.2, 12, 5.4, 16, 17, or 16.5 on a normalized dose basis for the patient; 4) 2.5 to 9, 2.6 to 8.5, 4.5 to 5.1, 2.5 to 8, 2.6 to 7.9, 4.2 to 6.7, 3.1 to 8, 5, 3.2 to 8.5, 4.5, 4.6, 5, 5.1, 2.5, 2.6, 4.2, 3.1, 9, 8.5, 5.1, 8, 7.9, or 6.7 a on a normal basis of emitted dose.

In some embodiments, based on the non-normalized corticosteroid dose, the AUCint provided by the corticosteroid solution is 1.6 to 2.5, 1.6 to 3.1, 1.5 to 3.5, 1.5 3.3, 2.5 to 3.3, 3.1, 1.5, 3.3, 1.6, or 2.5 times higher than the AUQnt provided by the suspension-based formulation when dose of corticosteroid in the solution and the suspension is approximately the same. Based on normalization to the nominal available corticosteroid dose, the AUCint provided by the corticosteroid solution is 1.75 to 6.5, 1.75 to 6.1, 2 to 6.5, 2 to 6.1 , 2 to 4.5, 2 to 4.4, 3.3, 3.2, 3.5, 3.4, 1.75, 6.5, 6.1, 2, 4.5, or 4, 4 times higher than the AUCint provided by the suspension based formulation. Based on normalization for lung corticosteroid dose, the AUCint provided by the corticosteroid solution is 1.2 to 3.5, 1.2 to 4, 1.2 to 3, 1.2 to 2.85, 1.5 to 3.5, 1.4 to 3.5, 2, 2.2, 2.3, 2.4, 1.2, 3, 4, 2.85, 1.5, 3.5, or 1.4 times higher than the AUCint provided by the suspension based formulation. Based on normalization for the patient's corticosteroid dose, the AUCjnt provided by the corticosteroid solution is 1.6 to 4.9, 1.5 to 5, 1.6 to 5, 1.6 to 3, 7, 1.6 to 3.6, 2 to 4.9, 1.9 to 4, 2.6, 1.5, 5, 1.6, 3.7, 3.6, 2, 4.9, 1, 9, or 4 times higher than the AUCjnf provided by the suspension based formulation. Based on normalization for the emitted dose of corticosteroids, the AUCinf provided by the corticosteroid solution is 1.5 to 6, 1.7 to 6, 1.9 to 6, 1.9 to 5.4, 2.3 to 5.8, 1.9 to 5.5, 1.9 to 5.8, 1.5, 6, 1.7, 1.9, 5.4, 2.3, 5.8, 5.8, 3.2, 3.5, or 3.6 times higher than the AUCinf provided by the suspension-based formulation.

In some embodiments, the AUCinf provided by the corticosteroid solution is at least 1.5, 1.6, 2, 2.5, 3 and 3.1 times higher than the AUCfn provided by the suspension-based formulation when the dose of corticosteroid in solution is about 2 times lower than the dose in suspension.

The formulation and system of the invention may provide an AUC0-Sh (pg * h / ml) from 2000 to 3000, 2500 to 2700, 2000, 3000, or 2600 on a non-standard corticosteroid dose basis. The formulation and system of the invention may provide an AUC, nf normalized dose (pg / ml / pg) of: 1) 2 to 3, 2.5 to 2.7, or 2.6 on a nominal standard loaded dose basis. for corticosteroids; 2) 3 to 4, 3.4 to 3.5, or 3.4 on a normalized dose basis for corticosteroid.

In some embodiments, based on the normalized (loaded) nominal dose of corticosteroid, the AUCo-eh provided by the corticosteroid solution is at least 1.7, 1.8, 1.9, or 2 times higher than AUC0. -8h provided by the suspension-based formulation when the dose of corticosteroid in the solution and the suspension is approximately the same. Based on normalization for the emitted dose of corticosteroids, the AUCo-eh provided by the corticosteroid solution is at least 1.5, 1.6, 2 times higher than the AUCo-sh provided by the suspension-based formulation.

The formulation and system of the invention may provide a C max (pg / ml) of 1600 to 1800, 1650 to 1750, or 1700 on a non-standard dose basis. The formulation and system of the invention may provide a standardized dose Cmax (pg / ml / pg) of: 1) 1 to 2, 1.6 to 1.8, or 1.7 on a nominal standard loaded dose basis. ; 2) 2 to 2.5, or 2.2 on a standard basis of emitted dose.

In some embodiments, based on the normalized (loaded) nominal dose of corticosteroid, the Cmax provided by the corticosteroid solution is at least 1.7, 1.8, 1.9, or 2 times higher than Cmax. provided by the suspension-based formulation when the dose of corticosteroids in the solution and the suspension is approximately the same. Based on normalization for the emitted dose of corticosteroid, the Cmax provided by the corticosteroid solution is at least 1.5, 1.6, 2 times higher than the Cmax provided by the suspension-based formulation.

In some embodiments, more than 20%, more than 25%, more than 29%, more than 35% of the emitted dose may be absorbed into the patient's bloodstream. In some embodiments, more than 40%, more than 50%, more than 55% of the patient dose may be absorbed into the patient's bloodstream. In some modalities, more than 10%, more than 12%, more than 15% of the nominal dose available may be absorbed into the patient's bloodstream.

Some aspects of the invention provide a method of administering or delivering the corticosteroid dose to the airway of a patient in need thereof, the method comprising administering or delivering the corticosteroid with a nebulizer, comprising a filler of an aqueous liquid formulation. , the formulation comprising an aqueous liquid carrier, sulfoalkyl ether cyclodextrin, and the corticosteroid dissolved therein, wherein during operation the system provides enhanced drug delivery, increased drug delivery rate, reduced treatment time, toxicity reduction, improved stability, enhanced bioabsorption, increased exit rate, increased total output, enhanced pharmacokinetic profile, reduced corticosteroid-related side effects, enhanced lung deposition, reduced oropharyngeal deposition, and / or improved nebulization performance over another system. comprising the nebulizer and the suspension-based formulation of corticosteroid. The systems may be operated under similar or dissimilar conditions.

The invention includes all combinations of the embodiments and aspects described herein. Accordingly, the invention includes the embodiments and aspects specifically described, broadly described, or narrowly described herein, as well as combinations thereof and sub-combinations of the individual elements of said embodiments and aspects.

These and other aspects of this invention will be apparent with reference to the following detailed description, examples, claims and accompanying figures.

Brief Description of the Figures

The following drawings are given by way of illustration only and are therefore not intended to limit the scope of the present invention.

Figure 1 is a graph of the hemolytic behavior of CAPTISOL® compared to the same for β-cyclodextrin of origin, commercially available hydroxypropyl derivatives, ENCAPSIN® (-3-4 degree of substitution) and MOLECUSOL® ( substitution grade -7-8), and two other sulfobutyl ether derivatives, SBE1-p-CD and SBE4-p-CD.

Figure 2 is an osmolality plot of SBE-CD containing solutions of varying degrees of substitution and e-β-CD containing solutions comprising similar concentrations of cyclodextrin derivative.

Figure 3 is a graph of the phase solubility of cyclodextrin (molar) concentration versus bude- deside (molar) concentration for γ-CD, ΗΡ-β-CD and SBE7-β-CD.

Figure 4 is a graph of the estimated percentage of nebulization composition emitted from three different nebulizers (PARI LC PLUS, HUDSON UPDRAFT II NEB-U-MIST, and MYSTIQUE) for each of four different nebulization compositions (PULMICORT suspension). RESPULES, 5% w / v solution of SBE7-β-CD, 10% w / v solution of SBE7-β-CD and 20% w / v solution of SBE7-β-CD).

Figures 5a-5b represent the droplet size data for nebulizing solutions with a PARI LC PLUS nebulizer. Figure 6 represents the droplet size data for nebulizing solutions with a HUDSON UPDRAFT II NEBUMIST nebulizer.

Figure 7 represents the droplet size data for nebulizing solutions with an MYSTIQUE ultrasonic nebulizer.

Figure 8 represents comparative data of Dv50 droplet sizes for nebulizing the composition with the three PARI LC PLUS, HUDSON UPDRAFT II NEBUMIST, and MYSTIQUE nebulizers.

Figure 9 is a graph depicting the relationship between SAE-CD concentration versus SAE-CD output rate in several different nebulizers.

Figures 10a-10b represent comparative droplet size data for nebulization solutions with the PAIRI LC PLUS and MYSTIQUE nebulizers of the PULMICORT RESPULES suspension and a modified PULMICORT RESPULES-based SAE-CD solution.

Figure 11 is a semi-log plot of the% initial concentration of budesonide R and S isomers in solutions with and without CAPTISOL against time at 60 ° C in solution.

Figure 12 is a semi-log plot of% initial budesonide concentration versus Lux hours when samples are exposed to fluorescent lamps.

Figure 13 is a phase solubility diagram for fluticasone propionate in the presence of several different cyclodextrins.

Figure 14 is a phase solubility diagram for mometasone furoate in the presence of several different cyclodextrins.

Figure 15 is a phase solubility diagram for esterified and non-esterified fluticasone in the presence of SAE (5-6) -γ-CD.

Figure 16 is a bar graph summarizing the aqueous solubility of beclomethasone dipropionate in the presence of various SAE-CD derivatives.

Figure 17 represents a plot of the geometric mean dose (corticosteroid, pg) to the patient versus the geometric mean AUC (pg * jr / ml) when budesonide is administered to patients according to

Example 17.

Figure 18 is a plot of the geometric mean dose (corticosteroid, pg) for the patient's lung versus the geometric mean AUC (pg * hr / ml) when budesonia is administered to patients according to Example 17.

Figure 19 represents a patient plot (corticosteroid, pg) versus AUC (pg * hr / ml) for each individual when budesonide is administered to patients according to Example 17.

Figure 20 represents a plasma concentration profile for budesonide for individual patients according to Example 17.

Figure 21 represents a plasma concentration profile for dog budesonide according to Example 31.

Figure 22 is a diagram detailing the approximate dose distribution of budesonides in administering a solution of the invention according to the procedure of Example 17.

Detailed Description of the Invention

The presently claimed formulation overcomes many of the undesired properties of other known aqueous inhalable corticosteroid-containing formulations in solution or suspension. By including SAE-CD in an inhaled liquid formulation containing corticosteroids, corticosteroids are dissolved. Unexpectedly, corticosteroid nebulization is improved in both the air-powered jet nebulizer and the ultrasonic nebulizer. In addition, corticosteroids exhibit more stability in the presence of SAE-CD than in their absence.

The inhalable formulation and system of the invention provides a pharmacokinetic profile with respect to the suspension formulation comprising approximately the same amount of corticosteroid and released under substantially the same conditions. The term "enhanced pharmacokinetic profile" is taken to mean a higher AUC (e.g. AUC or AUC (o -> □) per pg of released or administered corticosteroid, higher Cmax per pg of released or administered costicosteroid, increased bioavailability , absorption or distribution of corticosteroids at the release site, a lower Tmax or a higher Tmax.

Alternatively, the inhalable formulation and system of the invention substantially provides the same pharmacokinetic profile or an enhanced pharmacokinetic profile with respect to a suspension formulation comprising approximately a larger amount of corticosteroid and released under substantially the same conditions. The corticosteroid in the formulation may be present at a dose that is less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 20%, and less than 10% of that in suspension.

Corticosteroids may be present in an amount sufficient for single or multiple doses. SAE-CD would be present in an amount sufficient to solubilize the corticosteroid when both are placed in the aqueous vehicle. The aqueous vehicle would be present in an amount sufficient to aid dissolution of the corticosteroid and form a nebulization solution of sufficient volume and sufficiently low viscosity to permit single or multiple dose administration with a nebulizer. SAE-CD may be present in solid form or in solution in the aqueous vehicle. The corticosteroid would be present as a dry powder / particle or suspended in the aqueous vehicle.

Commercially available ultrasonic or pulsed membrane jet actuated nebulizers include AERONEB® (Aerogen, San Francisco, CA), PARI LC PLUS®, PARI BOY® Neo PARI DURANEB® (PARI Respiratory Equipment, Inc., Monterey, CA), MIC ROAIR® (Omron Healthcare, Inc., Vernon Hills, Illinois), HALOLITE® (Profile Therapeutics Inc, Boston, MA), RESPIMAT® (Boehringer Ingelheim Ingelheim, Germany) ), AERODOSE® (Aerogen, lnc, Mountain View, CA), OMRON ELITE® (Omron Healthcare, lnc, Vernon Hills, Illinois), OMRON MICROAIR® (Omron Healthcare, lnc, Vernon Hills, Illinois), MABISMIST® Il (Mabis Healthcare, Inc1 Lake Forest, Illinois); LUMISCOPE® 6610 (The Lumiscope Company, lnc, East Brunswick, New Jersey); AIRSEP MYSTIQUE® (Air-Sep Corporation n, Buffalo, NY), ACORN-1 and ACORN-II (Vital Signs, Inc, Totowa, New Jersey), AQUATOWER® (Medical Industries America, Adel, lowa), AVA-NEB (Hudson Respiratory Care Incorporates ted, Temecula, California), CIRRUS (Intersurgical Incorporated, Liverpool, New York), DART (Professional Medical Products, Greenwood, South Carolina), DEVILBISS® PULMO AIDE (DeViIbiss Corp; Somerset1 Pennsylvania), DOWNDRAFT® (Marquest, Englewood, Colorado), FAN JET (Marquest, Englewood, Colorado), MB-5 (Mefar, Bovezzo, Italy), MISTY NEB ® (Baxter, Va - lencia, California), SALTER 8900 (Salter Labs, Arvin, California), SIDESTRAM® (Medic-Aid, Sussex, UK), UPDRAFT-II® (Hudson Respiratory Care; Temecula, California), WHISPER JET ® (Marquest Medical Products, Englewood, Colorado), AIOLOS® (Aiolos Medicnnsk Teknik, Karlstad, Sweden), INSPIRON® (Intertech Resources, Inc., Bannockburn, Illinois), OP-TIMIST® ( Unomedical Inc., McAIIen, Texas), PRODOMO®, SPIRA® (Respiratory Care Center, Hameenlinna, Finland), AERx® (Aradigm Corporation, Hayward, California), SONIK® LDI Nebulizer (Evit Labs, Sacrament, California), and the SWIRLER® Radioaerosol System (AMICI, Inc., Spring City, PA). Nebulizers nebulizing liquid formulations containing no propellants are suitable for use with the compositions provided herein. Any of these and other known nebulizers may be used to distribute the formulation of the invention, including but not limited to the following: nebulizers are available from, Pari GmbH (Starnberg, Germany), DeViIbiss Healthcare (Heston, Middlesex, UK), Healthdyne , Vital Signs, Baxter, Allied Health Care, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana, Siemens, Aerogen, Medical Medain, Aerosol Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy), Henleys Medical Supplies (London, UK), Intersurgical (Berkshire, UK) , Lifecare Hospital Supplies (Leies, UK), Medic-Aid Ltd. (West Sussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Ltd. (Surrey, UK), and many others. AERx and RESPIMAT nebulizers are described by D.E. Geller (Respir. Care (2002) 47 (12), 1392-1404), the entire disclosure which is incorporated by reference.

Nebulizers for use herein include but are not limited to jet nebulizers (optionally sold with compressors), ultrasonic nebulizers, and others. Illustrative jet nebulizers for use here include Pari LC plus / ProNeb, Pari LC plus / ProNeb Turbo, Pari LC Plus / Hard Neb 1000 & 2000 Pari LC plus / Walkhaler, Pari LC plus / Pari Master, Pari LC star, Omron CompAir XL Portable Nebulizer System (NE-C18 and JetAir Available Nebulizer), Omron Compare Elite Compressor Nebulizer System (NE-C21 Nebulizer and Elite Air Reusable Nebulizer), Nebulizer Pari LC Plus or Pari LC Star with Proneb Ultra compressor, Pulomo-aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport, Inspection η Healthdyne 626, Pulmo-Neb Traverler, DeViBiss 646, Whisper Jet, Acorn II, Misty-Neb, Allied aerosol, S-chuco Home Care, Lexan Plasic Pocet Neb, SideStream Hand Held Neb, Mobil Mist, Up-Draft, Up-Draft II, T-Up-Draft, ISO-NEB, Ava-Neb, Micro Mist , and PuImoMate. Illustrative ultrasonic nebulizers for use here include MicroAir, UItraAir, Siemens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk Ultrasonic Nebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer, Medisana Ultrasonic Nebulizer, Microstrat Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer. Other nebulizers for use here include the 5000 Electromagnetic Neb, the 5001 Electromagnetic Neb 5002 Rotary Piston Neb, the Lumineb I Piston Nebulizer 5500, the Aeroneb Portable Nebulizer System, the Aerodose ™ Inhaler, and the AeroEcIipse Breath Actuated Nebulizer. Exemplary vibrating membrane, mesh or plate nebulizers are described by R.Dhand (Respiratory Care, (December 2002), 47 (12), p. 1406-1418), the entire description of which is hereby incorporated by reference.

Other suitable nebulizers are described in United States Patent Nos. 5,954,047, No. 6,026,808, No. 6,095,141, and No. 6,527,151, the entire disclosures of which are hereby incorporated by reference.

The present invention provides SAE-CD formulations, wherein SAE-CD is a compound of Formula I:

Formula 1

<formula> formula see original document page 49 </formula>

η is 4, 5 or 6;

R1, R2, R3, R4, R5, R6, R7, Re and R9 are each independently -O- or a group -0- (C2 -C6 alkylene) -SO3 ", where at least one of R1 - R9 is independently a group -0- (C2 -C6 alkylene) -SO3, preferably a group -O- (CH2) mSOa ', where m is 2 to 6, preferably 2 to 4, (e.g. -OCH2CH2CH2SO3 "or -0CH2CH2CH2CH2S03"); and

S1, S2, S3, S4, S5, S6, S7, S8 and S9 are each independently a pharmaceutically acceptable cation which includes, for example, H +, alkali metals (eg Li +, Na +, K +), alkaline earth metals (e.g. Ca + 2, Mg + 2), ammonium ions and amine cations such as (C1 -C6) alkylamines, piperidine, pyrazine, (C1 - C6) alkanolamine and (C4 -C6) cycloalkanolamine.

Illustrative embodiments of the SAE-CD derivative of the invention include those derivatives of Formula II (SAEx-a-CD), wherein "x" ranges from 1 to 18; of Formula III (SAEy-p-CD), wherein "y" ranges from 1 to 21; or Formula IV (SAEz-y-CD), wherein "z" ranges from 1 to 24, such as:

SAEx-g-CP SAEv-B-CD SAEz-y-CD Name

SEEx-a-CD SEEy-p-CD SEEz-y-CD Sulfoethyl ether CD

SPEx-a-CD SPEy-p-CD SPEz-y-CD Sulfopropyl ether CD

SBEx-a-CD SBEy-p-CD SBEz-y-CD Sulfobutyl ether CD SAEx-a-CD SAEv-B-CD SAEz- ^ CD Name

SPtEx-a-CD SPtEy-p-CD SPtEz-y-CD Sulfopentyl Ether CD SHEx-a-CD SHEy-p-CD SHEz-y-CD Sulfoexyl Ether CD

"SAE" represents a sulfoalkyl ether substituent attached to a cyclodextrin. The values "x", "y" and "z" represent the average degree of substitution as defined herein in terms of the number of sulfoalkyl ether groups per CD molecule.

The SAE-CD used is described in US Patents. Nos. 5,376,645 and No. 5,134,127 to Stella et al., The entire descriptions of which are hereby incorporated by reference. U.S. Patent No. 3,426,011 to Parmeter and others describes anionic cyclodextrin derivatives having sulfoalkyl ether substituents. Lammers et al. (Recl. Trav. Chim. Pays-Bas (1972), 91 (6), 733-742); Staerke (1971), 23 (5), 167-171) and Qu et al. (J. Inclusion Phenom. Macro. Chem., (2002), 43, 213-221) describe sulfoalkyl ether-derived cyclodextrins. U.S. Patent No. 6,153,746 to Shah and others describes a process for the preparation of cyclodextrin sulfoalkyl ether derivatives. A SAE-CD can be made according to the descriptions of Stella et al., Parmerter et al., Lammers et al. Or Qu et al. And if processed to remove the major portion (> 50%) of the cyclodextrin. of non-derivative origin, used in accordance with the present invention. SAE-CD may contain from 0% to less than 50% by weight of cyclodextrin of non-derivative origin.

The term "alkylene" and "alkyl" as used herein (for example in the group -0- (C2 -C6 alkylene) SO3 "or alkylamines) include divalent alkylene groups and linear monovalent alkyl groups. --saturated and branched, saturated and unsaturated (i.e. containing a double bond), respectively The term "alkanol" in this text also includes both saturated and unsaturated linear cyclic and branched alkyl components of the alkanol groups wherein the hydroxyl groups may be located at any position on the alkyl moiety The term "cycloalkanol" includes unsubstituted or substituted cyclic alcohols (e.g. methyl or ethyl). - containing a mixture of cyclodextrin derivatives having the structure specified in formula (I), where the total composition contains on average at least 1 and up to 3n + 6 portions of alkylsulfonic acid per cycle molecule. Dextrin The present invention also provides compositions containing a single type of cyclodextrin derivative, or at least 50% of a single type of cyclodextrin derivative. The invention also includes formulations containing cyclodextrin derivatives having a narrow or broad substitution degree and high or low. These combinations may be optimized as necessary to provide cyclodextrins having particular properties.

The present invention also provides compositions containing a mixture of cyclodextrin derivatives, wherein two or more different types of cyclodextrin derivatives are included in the composition. Different types are intended for cyclodextrins derived with different types of functional groups, for example hydroxyalkyl and sulfoalkyl, rather than the heterogeneous nature of derived cyclodextrins due to their varying degrees of substitution. Each different independent type may contain one or more functional groups, for example SBE-CD, where the cyclodextrin ring has only sulfobutyl functional groups, and hydroxypropyl-ethyl-p-CD, where the cyclodextrin ring has both hydroxypropyl functional groups and ethyl functional groups. The amount of each type of cyclodextrin derivative present may be varied as desired to provide a mixture having the desired properties.

Illustrative SAE-CD derivatives include SBE4-P-CD, SBE7-p-CD, SBE11-p-CD, SBE3.4-y-CD, SBE4.2-y-CD, SBE4. 9-y-CD, SBE5.2-y-CD, SBE6.1-y-CD, SBE7.5-y-CD, SBE7.8-y-CD and SBE5-y-CD, which correspond to the SAE-CD derivatives of formula I, where η = 5, 5, 5, and 6; m is 4; and there are on average 4, 7, 11 and 5 sulfoalkyl ether substituents present respectively. These SAE-CD derivatives increase the solubility of poorly water-soluble active agents to varying degrees. Since SAE-CD is a polyanionic cyclodextrin, it can be provided in different salt forms. Suitable counterions include cationic atoms or organic molecules and cationic inorganic atoms or molecules. SAE-CD may include a single type of counterion or a mixture of different counterions. The properties of SAE-CD can be modified by changing the identity of the present counterion. For example, a first salt form of SAE-CD may have a greater corticosteroid stabilizing and / or solubilizing capacity than a different second salt form of SAE-CD. Also, a SAE-CD having a first degree of substitution may have a stabilizing and / or solubilizing corticosteroid capacity greater than a second SAE-CD having a different degree of substitution. The increased solubilization of one corticosteroid by one SAE-CD against another is demonstrated by the data in the following tables, which represent the molar solubility for fluticasone propionate with different SAE-CD at concentrations around 0.03 to 0. , 12M, so that the solubilizing capacity approximately follows this order of classification over this SAE-CD concentration range: SBE5.2-y-CD> SPE5.4-y-CD> SBE6.1-y- CD> SBE9.7-γ-CD »SBE7-a-CD> SBE6.7-p-CD> SPE7-p-CD. For the methadone furoate, the solubilizing capacity approximately followed this order of classification over this SAE-CD concentration range: SBE9.7-y-CD> SBE6.1-y-CD> SBE5.2-Y-CD »SPE5.4-y-CD> SBE7-cc-CD> SBE6.7-p-CD> SPE7-P-CD. Differences were also observed for the binding of budesonide and triamcinolone with specific SAE-CD modalities. According to this invention, SAE-γ-CD binds a better corticosteroid than a SAE-β-CD. Also, SAE-p-CD binds a better budesonide than a SAE-a-CD. The data is summarized in FIGS. 13-14. <table> table see original document page 53 </column> </row> <table>

Alpha-cyclodextrin-enhanced steroid solubility

<table> table see original document page 53 </column> </row> <table> <table> table see original document page 54 </column> </row> <table> The inventors also found that SAE-y- CD is particularly suitable for use in complex formation of esterified and non-esterified corticosteroids compared to the complex formation of the same corticosteroids with SAE-p-CD or SAE-a-CD. The above table also summarizes the phase solubility data depicted in FIG. 15 for fluticasone and fluticasone propionate with different SAE-γ-CD species having a degree of substitution in the range of 5-10.

The present inventors have also found that SAE-γ-CD is also much more effective in binding to a particular esterified corticosteroid regioisomer than is SAE-β-CD or SAE-a-CD. The procedure set forth in Example 18 details the comparative assessment of the binding of SAE-y-CD and SAE-p-CD with a series of structurally related corticosteroid derivatives. The table below summarizes the results of a study comparing SBEx-y-CD binding, where χ represents the mean degree of substitution of SBE-p-CD derivatives and derivatives with the different forms of beclomethasone. <table> table see original document page 56 </column> </row> <table> Survival study shows that in the presence of SBE (3.4) γ-CD (0.04 M) all forms of beclomethasone were present. at or near its highest solubilities. B17P, the active metabolite of BDP, has the highest solubility of esterified beclomethasone forms in any of the derived CDs. Results indicate that SBE-γ-CD complexes with beclomethasone dipropionate better than Captisol or γ-CD alone. Of the SAE-CD derivatives evaluated, the optimal degree of SBE γ-CD substitution, which provides the largest increase in BDP solubility, is DS = 3.4, and solubility decreases almost linearly as degree of substitution increases. This is true for both 24 h and 5 day equilibrium times. Thus, in terms of BDP solubility with SAE-CD: SBE (3.4) γ-CD> SBE (5.2) γ-CD> SBE (6.1) γ-CD> SBE (7.5) γ-CD> γ-CD> Captisol (SBE7-CD). The data is summarized in FIG. 16. Therefore, the present inventors have found that the α-clodextrin SAE-CD derivatives are unexpectedly better at solubilizing corticosteroids than are the SAE-β-CD derivatives. In addition, SAE-CD-based formulations are suitable for use in inhalable formulations, contrary to the description of Worth et al. (Above), which suggests that SAE-CD derivatives are not.

By "complexed form" is meant "being part of a clathrate or inclusion complex with" that is, a therapeutic agent in the form of complex is part of a clathrate or inclusion complex with a cyclodextrin derivative. By "main portion" is meant at least about 50% by weight. Thus, a formulation according to the present invention may contain an active agent of which more than about 50% by weight complexes with a cyclodextrin. The actual percentage of active agent in complex form will vary according to the equilibrium constant of complex formation that characterizes complex formation of a specific cyclodextrin with a specific active agent. The invention also includes embodiments wherein the active agent does not complex with cyclodextrin or where a secondary portion of the active agent complexes with the derived cyclodextrin. It should be noted that a SAE-CD1 or any other anionic derived cyclodextrin may form one or more ionic bonds with a positively charged compound. This ionic association can occur regardless of whether the positively charged compound complexes with cyclodextrin by inclusion in the cavity or by forming a salt bridge.

Binding of a drug to derived cyclodextrin may be improved by including an acid or base together with the drug and cyclodextrin. For example, the binding of a basic drug to cyclodextrin could be enhanced by inclusion of an acid along with the basic drug and cyclodextrin. Also, the binding of an acidic drug with cyclodextrin could be improved by including a base (alkaline material) together with the acidic drug and cyclodextrin. Binding of a neutral drug could be enhanced by including a basic, acidic or other neutral compound together with the neutral drug and cyclodextrin. Suitable acidic compounds include inorganic and organic acids. Examples of inorganic acids are mineral acids such as hydrochloric and hydrobromic acid. Other suitable acids include sulfuric acid, sulfonic acid, sulfenic acid, and phosphoric acid. Examples of organic acids are aliphatic carboxylic acids such as acetic acid, ascorbic acid, carbonic acid, citric acid, butyric acid, fumaric acid, glutaric acid, Qolicic acid, α acid - ketoglutaric acid, lactic acid, malic acid, malabolic acid, maleic acid, malonic acid, oxalic acid, pimelic acid, propionic acid, succinic acid, tartaric acid, or tartronic acid. Aliphatic carboxylic acids containing one or more oxygen substituents on the aliphatic chain are also useful. A combination of acids may be used.

Suitable basic compounds include inorganic and organic bases. Suitable inorganic bases include ammonia, metal oxide and metal hydroxide. Suitable organic bases include primary amine, secondary amine, tertiary amine, imidazole, triazole, tetrazole, pyrazole, indole, diethanolamine, triethanolamine, diethylamine, methylamine, tromethamine (TRIS). ), aromatic amine, unsaturated amine, primary thiol, and secondary thiol. A base combination can be used.

An anionic derived cyclodextrin may complex or otherwise bind with an acid ionizable agent. As used herein, the term acid ionizable agent is considered to mean any compound that becomes, or is, ionized in the presence of an acid. An acid ionizable agent comprises at least one acid ionizable functional group that becomes ionized when exposed to acid or when placed in an acidic medium. Illustrative acid ionizable functional groups include a primary amine, secondary amine, tertiary amine, quaternary amine, aromatic amine, unsaturated amine, primary thiol, secondary thiol, sulfonium, hydroxyl, enol and others known to those of common skill in chemical techniques.

The degree to which an acid ionizable agent is bound by non-covalent ionic bonding against inclusion complex formation can be determined spectrophotometrically using methods such as 1 H-NMR, 13 C-NMR, circular dichroism, e.g. and by analyzing the phase solubility data for the acid ionizable agent and anionic derived cyclodextrin. One of ordinary skill in the art will be able to use these conventional methods to approximate the amount of each type of bond that is occurring in solution to determine whether or not the bond between species is predominantly occurring by noncovalent ionic bonding. or inclusion complex formation. An acid ionizable agent that binds to cyclodextrin derived by both means will generally exhibit a biphasic phase solubility curve. Under conditions where non-covalent ionic bonding predominates over inclusion complex formation, the amount of inclusion complex formation as measured by NMR or circular dichroism will be reduced, although the phase solubility data indicates significant binding between the species under these conditions; In addition, the intrinsic solubility of the acid ionizable agent as determined from the phase solubility data will generally be higher than expected under these conditions. As used herein, the term noncovalent ionic bond refers to a bond formed between an anionic species and a cationic species. The bond is non-covalent such that the two species together form a salt or pair of ions. An anionic derived cyclodextrin provides the anionic species of the ion pair and the acid ionizable agent provides the cationic species of the ion pair. Since an anionic derivative cyclodextrin is multivalent, an SAE-CD can form an ion pair with one or more acid ionizable agents.

Origin cyclodextrins have limited water solubility compared to SAE-CD and HPCD. Non-derived α-CD has a water solubility of about 14.5% w / v at saturation. Non-derived β-CD has a water solubility of about 1.85% w / v at saturation. Non-derived γ-CD has a water solubility of about 23.2% w / v at saturation. Dimethyl beta-cyclodextrin (DMCD) forms a 43% w / w aqueous solution at saturation. SAE-CD may be combined with one or more other cyclodextrins or cyclodextrin derivatives in the inhalable solution to solubilize the corticosteroid.

Other water-soluble cyclodextrin derivatives which may be used in accordance with the invention include hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and additional mixed ethers. methyl or ethyl groups such as alpha-, beta- and gamma-cyclodextrin methylhydroxyethyl, ethylhydroxyethyl and ethylhydroxypropyl ethers; and alpha, beta- and gam-cyclodextrin maltosyl, glycosyl and maltotriosyl derivatives, which may contain one or more sugar residues, for example glycosyl or di-glycosyl, maltosyl or dimaltosyl, as well as their various mixtures. for example, a mixture of maltosyl and dimaltosyl derivatives. Specific cyclodextrin derivatives for use herein include hydroxypropyl beta-cyclodextrin, hydroxyethyl beta-cyclodextrin, hydroxypropyl gamma-cyclodextrin, hydroxyethyl gamma-cyclodextrin, dihydroxypropyl beta-cyclodextrin, glycosyl alpha cyclodextrin, glycosyl beta cyclodextrin, diglycosyl beta cyclodextrin, maltosyl alpha cyclodextrin, maltosyl beta cyclodextrin, maltosyl gamma cyclodextrin, maltotriosyl beta cyclodextrin , maltotriosyl gamma-cyclodextrin and dimaltosyl beta-cyclodextrin, and mixtures thereof such as maltosyl beta-cyclodextrin / dimaltosyl beta-cyclodextrin, as well as methyl beta-cyclodextrin. Procedures for preparing such cyclodextrin derivatives are well known, for example from Bodor United States Patent No. 5,024,988, issued June 18, 1991, and the references cited therein. Other suitable cyclodextrins for use in the present invention include carboxyalkyl thioether derivatives such as ORG 26054 and ORG 25969 prepared by ORGANON (AKZO-NOBEL), hydroxybutenyl ether derivatives prepared by EASTMAN, sulfoalkyl ether derivatives -hydroxyalkyl, sulfoalkylalkyl ether derivatives, and other derivatives, as described in Pre-Deferred Patent Applications Publication No. 2002/0128468, No. 2004/0106575, No. 2004/0109888, and No. 2004/0063663, or U.S. Patent Nos. 6,610,671, No. 6,479,467, No. 6,660,804, or No. 6,509,323.

Β-β-CD can be obtained from Research Diagnostics Inc. (Flander, NJ). ΗΡ-β-CD is available with different degrees of substitution. Illustrative products include ENCAPSIN® (degree of substitution ~ 4; ΗΡ4-β-00) and MOLECUSOL® (degree of substitution ~ 8; ΗΡδ-β-CD); however, modalities including other degrees of substitution are also available. Since HPCD is nonionic, it is not available in salt form.

Dimethyl cyclodextrin is available from FLUKA Chemie (Buffets, CH) or Wacker (lowa). Other derivative cyclodextrins suitable for the invention include water soluble derivative cyclodextrins. Illustrative water soluble derived cyclodextrins include carboxylated derivatives; sulfated derivatives; alkylated derivatives; hydroxyalkylated derivatives; methylated derivatives; and carboxy-cyclodextrins, for example succinyl-cyclodextrin (SCD), and 6A-amino-6A-deoxy-N- (3-carboxypropyl) β-cyclodextrin. All of these materials may be prepared according to methods known in the prior art. Suitable derived cyclodextrins are described in Modified Cvclodextrins: Scaffolds and Templates for Supramolecular Chemistry (Eds. Christopher J. Easton, Stephen F. Lincoln, Imperial College Press, London, UK, 1999) and New Trends in Cvclodextrins and Derivatives. (Ed. Dominique Duchene, Santé Editions, Paris, France, 1991).

% W / w solutions of β-cyclodextrin sulfobutyl ether (CAPTISOL, CyDex Inc., degree of substitution = 6.6), 2-hydroxypropyl-p-cyclodextrin (ΗΡ-β-CD, CERESTAR, degree of substitution = 5.5), succinylated β-cyclodextrin (S-CD, Cyclolab), and 2,6-di-o-methyl-β-cyclodextrin (DM-CD, Fluka) were prepared at their native pH or buffered as required . The derivatives of sulfoalkyl ether γ-CD and sulfoalkyl ether α-CD were obtained from CyDex, Inc. (Lenexa, KS) and the University of Kansas (Lawrence, KS).

The amount of derived cyclodextrin required to provide the desired effect will vary according to the materials comprising the formulation.

Different cyclodextrins are capable of solubilizing a corticosteroid to different degrees. FIG. 3 represents a molar phase solubility curve for budesonide with ΗΡ-β-CD, SBE7-β-CD, and γ-CD compared to water. The inventors have found that SAE-CD is superior to other cyclodextrins and cyclodextrin derivatives in budesonide solubilization. On a molar basis, SBE-β-CD is a better budesonide solubilizer than ΗΡ-β-CD. In addition, the solubilizing capacity among SAE-CD derivatives followed approximately this classification order for budesonide over a 0.04 to 0.1 M SAE-CD concentration range: SBE5.2- y-CD-SPE5.4-y-CD> SBE6.1-y-CD> SBE7-a-CD> SBE9.7-Y-CD-SBE6.7-β-CD> SPE7 ^ -CD. For example, a 0.1 M concentration of SBE7-β-CDC was able to solubilize a greater amount of budesonide than γ-CD or ΗΡ-β-CD. In addition, nebulizable formulations containing SAE-CD provide a higher nebulization corticosteroid output rate compared to γ-CD or ΗΡ-β-CD administered under otherwise similar conditions.

It has been unexpectedly found that nebulization of Captisol solutions provides several advantages over other cyclodextrins. The droplets leaving the nebulizer are of a more advantageous size and Captisol solutions are nebulized faster than similar solutions of other Cyclodextrins. The table below shows that the mean particle size (Dv50) of Captisol solutions is smaller than that of ΗΡ-β-CD or γ-CD. More importantly, as seen in the table below, Dv90 shows that the other cyclodextrins had a significant number of very large droplets. The data (Malvern particle size) was obtained for each formulation as emitted from a PARI LC PLUS nebulizer equipped with a PARI PROENB ULTRA air compressor. Smaller droplet size is preferred for an inhalable composition as it allows for a deeper distribution of active agents, such as a corticosteroid, into the lung.

<table> table see original document page 63 </column> </row> <table>

This advantage is further shown in the output rate of these solutions. The table below shows that Captisol is emitted from the faster nebulizer, and also to a greater degree, than the other cyclodextrins, so the nebulizer output rate is higher when Captisol is nebulized. <table> table see original document page 64 </column> </row> <table>

Misting is interrupted when the sound changes (time to crackle) or visible particles are no longer produced.

The advantage of Captisol has been further demonstrated by preparing solutions containing budesonide dissolved in various cyclodextrins and comparing its nebulization performance with the performance of commercial PULMICORT® RESPULES®, a unit dose formulation based on suspension, commercially available. The suspension obtained from several PULMICORT® unit dose ampoules was combined to form a multipurpose suspension-based unit dose formulation, and the SAE-CD powder (specifically, CAPTISOL). -β- or γ-cyclodextrin was added to obtain a budesonide solution concentration of 0.25 mg / ml. These budesonide-containing solutions contained 5% w / v Captisol (P5C), 1% w / v gamma-CD (PItCD) and 5% w / v hydroxypropyl beta-cyclodextrin (P5HPpCD). Each was prepared at least 30 minutes before the entire test. All three formulations were clear, colorless solutions. (Note: A 250 mg / mL solution of budesonide cannot be obtained in a 5% w / v solution of γ-cyclodextrin as it exhibits "B" type solubility behavior.) A 2 ml aliquot The suspension or solution was placed in the same Pari LC Plus nebulizer configuration and the amount of budesonide in the droplets emitted was determined by collecting them on a filter and measuring budesonide using HPLC. As shown in the table below, the total output rate (μ.ς of collected bude-sonide / time to crackle) for each suspension or solution.

<table> table see original document page 65 </column> </row> <table>

The exit rate is the highest for Captisol solution, indicating that an equivalent amount of drug can be delivered over a shorter period of time. Under the conditions used, β-CD is unable to solubilize an equivalent amount of corticosteroid due to the limited solubility of β-CD in water.

The present invention may be used with other aqueous suspension-based formulations which may be adapted for nasal delivery or pulmonary delivery. Illustrative aqueous suspension formulations include the UDB formulation (Sheffield Pharmaceuticals, Inc.), VANCENASE® AQ (beclomethasone dipropionate aqueous suspension; Schering Corporation no. Kenilworth, NJ), ATOMASE® ( beclomethasone dipropionate aqueous suspension; Douglas Pharmaceuticals Ltd., Aukland, Australia), BECONASE® (beclomethasone dipropionate aqueous suspension; Glaxo Wellcome), NASACORT AQ® (triamcinolone acetonide nasal spray, Aventis Pharmaceuticals) , TRI-NASAL® (aqueous triamcinolone acetonide suspension; Muro Pharmacaceuticals Inc.) and AERO-BID-M® (flunisolide inhalation aerosol, Forest Pharmaceuticals), NA-SALIDE® and NASAREL® (nasal spray flunisolid, Ivax Corporation η), FLONASE® (fluticasone propionate, GIaxoSmithKIine), and NASONEX® (mometasone fuorate, Schering-Plow Corporalion n).

The suspension formulation may comprise corticosteroids present in particulate, microparticulate, nanoparticulate or nanocrystalline form. Thus, an SAE-CD may be used to improve the administration of a corticosteroid suspension-based unit dose formulation. In addition, SAE-CD performs better than other cyclodextrin derivatives.

According to one embodiment, SAE-CD (in solid or liquid form) and a suspension-based unit dose formulation comprising corticosteroids are mixed. SAE-CD is present in an amount sufficient to increase the amount of solubilized corticosteroids, that is, decrease the amount of non-solubilized corticosteroids therein. Prior to administration, the liquid may optionally be aseptically filtered or terminally sterilized. The liquid is then administered to a patient by inhalation using a nebulizer. As a result, the amount of drug the patient receives is greater than the patient would have received if the unchanged suspension formulation had been administered.

According to another embodiment, SAE-CD (in liquid form, as a ready-to-use liquid or as a concentrate) and a solid unit dose formulation comprising corticosteroids are mixed to form a liquid formulation. SAE-CD is present in an amount sufficient to solubilize a substantial portion of the corticosteroid. The liquid is then administered via inhalation using a nebuliser.

According to another embodiment, SAE-CD (in solid form) and a solid unit dose formulation comprising corticosteroids are mixed to form a solid mixture to which an aqueous liquid carrier is added in a sufficient amount. to form a nebulizable formulation. Mixing and / or heating is optionally employed in addition of the liquid carrier to form the formulation. SAE-CD is present in an amount sufficient to solubilize a substantial portion of the corticosteroid. The formulation is then administered via inhalation using a nebulizer. The size of the reservoir varies from one type of nebulizer to another. The volume of the liquid formulation may be adjusted as required to provide the volume required for loading a particular type or brand of nebulizer into the reservoir. The volume can be adjusted by adding additional liquid vehicle or additional solution containing SAE-CD. In general, the reservoir volume of a nebulizer is around 10 μΙ to 100 ml. Ultrasonic and vibrating mesh nebulizers / vibrating plate / vibrating cone / vibrating membrane, preloaded reservoir ranges including release nozzle typically have a reservoir volume of 10 μΙ to 6 ml or 10 μΙ to 5 ml. Low-volume nebulizers provide the advantage of shorter administration times over large-volume nebulizers.

Example 28 details a procedure for preparing a solution of the invention for use with a low volume nebulizer (low reservoir volume and / or low residual reservoir volume) such as an AERx nebulizer. The solutions of the invention may be nebulized with any nebulizer; however, with an AERx release system that coordinates both inhalation and release processes to optimize deep lung penetration, an initial sample volume of about 10 to 100, or 50 μΙ can be used for loading. the AERx Range unit dose container. Administration of this solution with the system makes it feasible for a therapeutic dose to be administered to a patient in a single puff (a single total inhalation by a patient, i.e. 3 to 5 seconds) by nebulization. Based on overall performance expectations and such devices where the delivered dose is 60 to 65% and subsequent lung doses are .65 to 85%, about 10 μg to 60 μg or 10 pg to 110 μg of budesonide can be expected to be delivered to the lung in a single dosing event using SAECD-prepared budesonide solutions.

Example 32 details a procedure for comparing nebulization parameters in four different nebulizers using a formulation of the invention and PULMICORT RESPULES (suspension based formulation). In each case, the formulation of the invention represents the suspension based formulation. The solution of the invention provides a 1.25, 1.4, 2.1, 3.3, 3.67, 1.25 to 3.7, or 1.25 to 4 fold increase in the amount of budesonide released. . Under the conditions tested, AIRSEP MYSTIQUE was more efficient in the emission / nebulization of the budesonide / SAE-CD formulation.

Unless otherwise specified, the term "dose", which is intended to include an effective dose, is used to mean a nominal dose, emitted dose, nominal available dose, patient dose, lung dose or other such term. of technique. The term "nominal dose" refers to an amount of corticosteroid placed in the reservoir of a nebulizer, wherein the volume of liquid in the reservoir is determined according to the size of the reservoir. The term "nominal available dose" refers to the amount of corticosteroid that is determined to be or may have been available to the patient when a formulation of the invention is administered by nebulization, but the formulation is not / has not been administered in its entirety. . The term "emitted dose" refers to the amount of corticosteroid emitted from a nebulizer. The term "patient dose" refers to the amount of corticosteroid released to and retina by a patient following administration of a formulation of the invention by nebulization. The term "lung dose" refers to the amount of corticosteroid released to and retained by a patient's lungs following administration of a formulation of the invention by nebulization.

In general, a unit dose formulation based on the single-use suspension of corticosteroids contains about 0.125, 0.25, 0.5, 1, 2, or about 0.125 to about 2 mg of corticosteroids suspended in about from 50 μΙ to 10 ml of liquid vehicle. Alternatively, corticosteroids are present in a concentration of about 20 mcg to about 30 mg corticosteroids per ml of suspension. As a result, about 10 to 500 mg SAE-CD, or 10 to 250 mg SAE-CD, or 10 to 300 mg SAE-CD, either in solid form or dissolved in a liquid carrier, are added. to each ml of suspension to dissolve a substantial portion of the corticosteroid and form a nebulizable corticosteroid unit dose liquid formulation and form a nebulizable unit dose liquid formulation which is then administered to a patient.

The formulation, method or system may employ a dose of about 1 pg to 20 mg, 1 pg to 10 mg, 0.01 mg to 10 mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg 5 mg, 0.125 mg 5 mg, 0.25 mg 5 mg, 0.5 mg 5 mg, 0.05 mg 2 mg, 0.1 mg 2 mg, 0.125 mg 2 mg, 0 mg , 25 mg to 2 mg, 0.5 mg to 2 mg corticosteroid. These dose amounts are suitable for the corticosteroids of the invention, in particular corticosteroids which are as lipidic as or more lipophilic than flunisolide, whose corticosteroids include beclomethasone, beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyride. ciclesonide, fluisolide, fluticasone, fluticasone propionate, mometasone, mometasone furoate, triamcinolone acetonide.

The formulation of the invention comprises a dose of corticosteroid in a solution volume of approximately 10 ml to 10 ml, 50 ml to 50 ml, 50 ml to 10 ml, 0.1 to 10 ml, 0.1 ml less than that 10 ml, 0.1 to 7.5 ml, 0.1 ml to 5 ml, 0.1 ml to 3 ml, 0.1 ml to 2 ml, 0.1 ml to 1 ml, 0.05 ml to 7.5 ml, 0.05 ml to 5 ml, 0.05 ml to 3 ml, 0.05 ml to 2 ml, or 0.05 ml to 1 ml.

Due to the wide range of nebulizer reservoir volumes and varying dose requirements between corticosteroids, a formulation of the invention may comprise 1 mg to 20 mg corticosteroids in 0.001 ml to 100 ml solution volume.

In general, a multipurpose suspension-based unit dose corticosteroid formulation contains approximately 0.125 to 2 mg of corticosteroid suspended in 1 to 100 ml of liquid carrier. Multipurpose formulation actually contains two or more unit doses of corticosteroids. Individual unit dose aliquots are taken from a multipurpose unit dose formulation, and individual unit doses are typically administered one at a time to a patient. As a result, about 10 to 500 mg SAE-CD, either in solid form or dissolved in a liquid carrier, is added to each ml of the suspension to dissolve a substantial portion of the corticosteroid and form a formulation. multipurpose unit dose liquid, which is then administered to a patient in individual unit dose aliquots.

One aspect of the invention is that a suspension-based unit dose formulation is converted to a liquid unit dose formulation prior to pulmonary administration via inhalation (from a mist mist) to a patient. Conversion may occur in the same container in which the suspension is provided, in a different container, or in a nebulizer reservoir. To form a liquid formulation, a substantial portion of the corticosteroid must be dissolved. As used in reference to the amount of dissolved corticosteroid, a "substantial portion" is at least 20 wt%, at least 30 wt%, at least 40 wt%, or at least 20 wt% and less than 50% by weight of corticosteroids. As used in reference to the amount of dissolved corticosteroid, a "major portion" is at least 50% by weight of corticosteroid.

It is well known that pharmacists working in drug combination can prepare and, in fact, prepare a suspension-based unit dose formulation comprising corticosteroids. Such pharmacists will now be able to prepare a single or multi-use liquid unit dose formulation by employing a method described herein. Alternatively, a patient undergoing corticosteroid treatment may transform the suspension-based formulation into a liquid formulation of the invention by employing a method described herein. Instead of preparing the liquid formulation from the suspension at the pharmacy, a kit containing the suspension formulation and SAE-CD may be prepared.

SAE-CD concentration in solution may be expressed on a weight to weight or weight to volume basis; however, these two units are convertible to each other. When a known weight of cyclodextrin is dissolved in a known weight of water, the% w / w cyclodextrin concentration is determined by dividing the weight of cyclodextrin in grams by the total weight (weight of cyclodextrin + water ), in square units, and multiplying by 100. When a known weight of cyclodextrin is dissolved to a known total volume, the% w / v cyclodextrin concentration is determined by dividing the weight of the cyclodextrin, in grams, by the total volume, in milliliters, and multiplying by 100. The correlation between the two percentages of cyclodextrin concentration was experimentally determined by preparing several cyclodextrin solutions in% w / w and measuring the density of each with a pycnometer at 25 ° C. The density (g / mL) of each CAPTISOL solution in% w / w is given in the table below.

<table> table see original document page 71 </column> </row> <table>

The resulting linear relationship readily enables the conversion of CAPTISOL concentrations expressed as% w / w to that of% w / v by the following equation:

% w / v = [(% w / w * slope) + y-intercept] *% w / w where slope and intercept values are determined from a linear regression of the density data in the table. For example, using the above equation, a 40% w / w CAPTISOL solution would be equivalent to a -48.3% w / v CAPTISOL solution.

The performance of an inhalable solution of the invention in a nebulizer may depend on the viscosity of the solution in its reservoir, the nebulization solution. The viscosity of an aqueous SBE7-β-CD solution changes with respect to concentration approximately as indicated in the above table. The viscosity of the inhalable composition can impact the percentage of nebulizer composition emitted from a nebulizer, the nebulized corticosteroid output rate and the droplet size distribution.

The amount of inhalable residual nebulizer composition left in the nebulizer reservoir may be greater for SAE-CD containing solutions than for a budesonide containing suspension. For example, Figure 4 is a graph of the estimated percentage of nebulization composition emitted from three different nebulizers (PARI LC PLUS, HUDSON UPDRAFT II NEB-U-MIST1 and MYSTIOUE) for each of four different nebulization compositions. (PULMICORT RESPULES suspension, 5% w / w SBE7-p-CD solution, 10% w / w SBE7-p-CD solution and 20% w / w SBE7-p-CD solution). PULMICORT RESPULES suspension was used as the control. PARI LC PLUS, MYSTIOUE and HUDSON nebulizers were used for comparison. The MYSTIOUE nebulizer was not able to effectively nebulize the suspension and concentrated SAE-CD solution (20% w / w), so they were not evaluated with this nebulizer. The results suggest that under the conditions tested, nebulization of the PULMICORT RESPULES suspension results in a higher percentage of nebulized composition, meaning that with the suspension less nebulization composition is left in the nebulizer reservoir at the end of nebulization, compared to the solution. In some cases, nebulization of the suspension resulted in the highest percentage by weight of total composition emitted by a nebulizer. In other words, under similar nebulization conditions, PARI LC PLUS and HUDSON nebulizers reduced the nebulization suspension volume more efficiently than nebulization solution; however, this did not correspond to the total amount of drug emitted by the nebulizer.

The output rate of a SAE-CD nebulization solution versus that of a suspension, each containing bude-sonide, was compared. A modified version of the method of Example 10 was followed to determine the output rate. The tables below summarize the observed data. <table> table see original document page 73 </column> </row> <table> Data obtained from a PARI LC PLUS nebulizer equipped with a PARI PRONEB ULTRA air compressor.

<table> table see original document page 74 </column> </row> <table> All of the above formulations contain approximately 250 p.g / mL budesonide. Samples identified as "P5C" contain 50 mg / mL (or about 5%) SBE7-p-CD.

The table below shows the nebulizer output rate for solutions containing various levels of SAE-CD.

<table> table see original document page 75 </column> </row> <table>

Surprisingly, nebulization of the SAE-CD-containing solution provided a higher budesonide exit rate than nebulization of the PULMICORT RESPULES suspension, although the nebulizer emitted a larger total amount of the suspension. Higher SAE-CD concentrations above 25% w / v resulted in slightly longer nebulization times and lower exit rates as viscosity exceeded an approximate upper limit.

Without being attached to a particular mechanism, it is believed that the nebulizer preferably nebulises the water (supernatant) of the suspension rather than the suspension particles, thereby causing an increase in the budesonide molar concentration in the suspension, in the reservoir. vatory.

Since corticosteroid is dissolved in the solution of the invention, this type of separation does not occur to a significant degree. As a result, the rate of increase in corticosteroid concentration in the reservoir is lower than it is with the suspension. Other support for this phenomenon is detailed in the following table:

<table> table see original document page 76 </column> </row> <table>

The above data were obtained by comparing the nebulization of a solution of the invention (CEB, SAE-CD, 5% w / v, 2 ml; budesonide, 250 μg / ml) and 2 ml suspension of PULMICORT RESPULES; budesonide, 250 μg / ml) using a PARI LC + equipped with a PARI PRONEB ULTRA air compressor. The budesonide concentration in the reservoir was measured at two minutes and at the time of spraying (TTS). The rate of increase in corticosteroid concentration (RIC) in the reservoir solution was then calculated for each formulation during each time interval. The ICN of the solution of the invention provided an approximately 48% decrease in ICN for two minutes and an approximately 42% decrease in ICN during TTS. In some modalities, the percentage decrease in the ICN ranges from 10% to 60%, 15% to 60%, 20% to 60%, 30% to 60%, or 40% to 60%. In some embodiments, the system may provide an ICN of 0 to 40, 1 to 40, 5 to 30, or 10 to 30 mcg corticosteroid / mL solution volume per minute of operation / nebulization.

Accordingly, the invention provides a system for nebulised corticosteroid administration comprising a nebulizer comprising a reservoir; and an inhalable aqueous composition comprising SAE-CD and a corticosteroid dose, whereby the system provides a reduced RIC for the corticosteroid in the reservoir compared to the Rlc provided by a suspension comprising approximately the same amount of corticosteroid and volume of corticosteroid. aqueous composition operated under approximately the same conditions.

Based on the above data, a concentration of 21.5 + 5% w / w SBE7-p-CD was identified as the approximate upper acceptable level for the tested nebulizer, "acceptable" being defined as the highest SBE7 concentration. -CD that can be used without developing excessive viscosity, which may adversely affect nebulization time and exit rate. The practical upper limit for SAE-CD concentration will vary between nebulizer formats. The highest acceptable concentration of SAE-CD in a liquid formulation for use in a nebulizer may vary according to the DS of the derivative, the sulfoalkyl functional group alkyl chain length, and / or the size of the CD ring. from SAE-CD.

For administration to the respiratory tract, particularly the lungs, a nebulizer is used to produce appropriately sized droplets. Typically, the particle size of the nebulizer-produced droplet for inhalation is in the range of about 0.5 to about 5 microns. If the droplets are desired to reach the lower regions of the respiratory tract, i.e. the alveoli and terminal bronchi, the preferred particle size range is from about 0.5 to about 2.5 microns. If the droplets are desired to reach the upper respiratory tract, the preferred range of particle sizes is between 2.5 microns and 5 microns.

As noted above, the viscosity of the nebulizer composition can impact droplet size and droplet size distribution. For example, the present formulations tend to form larger droplets, in terms of Dv50, at lower concentrations, and thus lower viscosity, of SAE-CD in the absence of bude-sonide. FIGS. 5a-5b represent the droplet size data for nebulizing inhalable compositions with a PARI LC PLUS nebulizer. For each of the figures, a MALVERN laser light scanner (Mastersizer S, Malvern Instruments Ltd., Malvern, Worcs, U.K.) was used to measure the MMAD. FIG. 5a represents the results obtained using γ-CD solutions of varying concentrations (5% w / v, 10% w / v and 20% w / v) in the absence of budesonide. The results indicate that γ-CD on its own would not behave acceptably in a nebulizer, since almost the entire mass of the solution is within an unacceptable droplet size range. Even with extensive recycle and droplet size selection by a nebulizer, a corticosteroid-containing γ-CD-based nebulization solution would require an extremely long dosing period due to the low mass percentage that is within the droplet size range. appropriate, especially since γ-CD is not an effective budesonide solubilizer at the concentrations tested.

In comparison, FIG. 5b represents the results obtained using the same nebulizer with the PULMICORT RESPULES suspension or a modified PULMICORT RESPULES solution containing SAE-CD at different concentrations (5% w / v, 10% w / v and 20% w / v) . With each of these samples, a significant portion of the nebulized mass is of a breathable size range. In addition, SAE-CD containing solutions apparently form droplets that are comparable in size to those of the nebulized suspension.

Figure 6 represents the droplet size data for nebulizing inhalable compositions with a HUDSON UPDRAFT Il NEBUMIST nebulizer loaded with PULMICORT RESPULS suspension or a solution containing SAE-CD at different concentrations (5% w / v , 10% w / v and 20% w / v). Compared to the PARI LC PLUS nebulizer, NEB-U-MIST forms a slightly larger particle size distribution, a significant portion of the nebulized mass is still in the appropriate size range. Thus, the nebulization solution prepared from the suspension and containing SAE-CD is suitable for use in a variety of different air-driven jet nebulizers.

The package insert for the PULMICORT RESPULES suspension specifies that the suspension should not be nebulized with an ultrasonic nebulizer. Figure 7 represents the droplet size data for nebulizing inhalable compositions with a MYSTIQUE ultrasonic nebulizer. The compositions include three different solutions containing SAE-CD. Unlike the suspension, the SAE-CD containing solution can be nebulized with an ultrasonic nebulizer. Thus, the invention provides a method of enhancing pulmonary distribution of corticosteroids in a suspension-based unit dose formulation from an ultrasonic nebulizer, the method comprising the step of including SAE-CD in the formulation in a sufficient amount to decrease the amount of undissolved corticosteroid in the suspension-based unit dose formulation.

The performance of nebulization compositions across a range of nebulizers is typically compared by comparing the Dv50 of the droplet size distribution for the respective compositions. Figure 8 represents the comparative data of the droplet sizes Dv50 for nebulizing an inhalable composition with the three aforementioned nebulizers. In each case, SAE-CD containing solutions are suitable for administration by nebulization over a range of concentrations. In addition, the droplet size distribution can be partially controlled by adjusting the SAE-CD concentration.

Figure 9 is a graph depicting the relationship between the SAE-CD concentration versus the SAE-CD output rate in several different nebulizers with different compressed air sources required for the specific configuration: jet driven nebulizers. RAIN-DROP-Rat, RAINDROP-Dog, PARI LC STAR-UNC1 PARI LC STAR-Rat PARI LC PLUS and DEVILBISS PULMO AIDE. Nebulizers have been used in a variety of configurations, including free standing as well as animal exposure chambers and / or individual exposure masks. In general, the data demonstrate that SAE-CD output increases with increasing SAE-CD concentration. Depending on the nebulizer used, the conditions under which the nebulizer is operated and the concentration of SAE-CD in solution, different maximum output rates may be obtained. For example, the maximum exit rate in Raindrop-Dog configuration is from a CAPTISOL concentration of 250 mg / mL.

Although nebulization of the PULMICORT RESPULES suspension with an ultrasonic nebulizer is not recommended, it can be obtained. Figures 10a-10b represent comparative droplet size data for nebulization solutions with the PARI LC PLUS and MYSTIQUE nebulizers of the PULMICORT RESPULES suspension and a modified PULMICORT RESPULES-based SAE-CD solution. PULMICORT RESPULES suspension, with and without 5% w / v SBE7-p-CD, was used as the test samples. The procedure of Example 12 was followed. FIG. 10a represents the data for Dv10 and Dv50 for solutions run on the PARI LC PLUS air-powered jet nebulizer and FIG. 10b represents the data for Dv10 and Dv50 for solutions run on the MYSTIQUE ultrasonic nebulizer. In each case, the droplet size data for the two different solutions is comparable. However, the budesonide exit rate for both solutions was significantly different. The use of SAE-CD in a nebulization composition, however, results in an increased budesonide output rate, regardless of the shape of the nebulizer. The invention thus provides a method of increasing the exit rate of a corticosteroid-containing suspension-based unit dose formulation being delivered by a nebulizer, the method comprising the step of including SAE-CD in the formulation. sufficient to increase the amount of corticosteroid dissolved in the formulation to form an altered formulation, so that the corticosteroid output rate for the altered formulation is greater than the corticosteroid output rate for the formulation. suspension.

Two pulsatile membrane nebulizers (AERONEB GO and U.S. Patent No. 6,962,151) were evaluated according to Examples 21 and 22, respectively, to determine the performance of the devices with a solution of the invention and to demonstrate. the utility of employing concentrated corticosteroid solutions in an efficient electronic nebulizer. Several in vitro parameters, important for the clinical use of corticosteroids, were determined and compared to these parameters of the solution formulation described in Example 6 and the 2 ml commercial reference suspension both in an air jet nebulizer. Total distribution / nebulization time (time to spray where aerosol production is no longer visible), MMAD droplet size and fine particle fraction parameters were obtained for each device. A cascade impactor was compromised with the output of each device to determine performance during nebulization and to characterize in vitro aerosol drug output.

The solution used in the AERONEB GO device was compared side by side with a RAINDROP air jet nebulizer employing a solution (0.5 ml) comprising budesonide (500 pg / 0.5 ml), CAPTISOL (10% w / v ), water, and Tween 80 (optional), wherein the solution was made by adding CAPTISOL to a budesonide particle suspension (RESPULES) as detailed below. In each device, the sample based on the control suspension was the RESPULES suspension (2 ml containing 500 pg budesonide). The RAINDROP nebulizer was equipped with a PARI PRONEB ULTRA compressor. The AERO-NEB GO micropump nebulizer has been equipped with the OnQ Aerosol Generator. Total bude- deside outflow at aerolization cessation (spraying) was quantified. The emitted dose and the fine particle dose were measured with the brush impactor. The solution in the Ί51 Patent nebulizer comprised budesonide, CAPTISOL, water, "and technetium-99 radiolabel in the form of diethylenediaminapentaacetic acid as a surrogate marker for budesonide. Data from two studies are summarized in the table below.

<table> table see original document page 81 </column> </row> <table> <table> table see original document page 82 </column> </row> <table>

* Normalized data for 500 pg budesonide in each nebuliser using total drug recovered.

+ Note: Nebulizers were operated 30 seconds after nebulization time ended to ensure complete NGI impactor emptying.

Using electronic pulsatile membrane nebulizers (AERONEB GO nebulizer and Ί51 Patent nebulizer), a single dose of corticosteroid release was completed within less than one minute. The RAINDROP nebulizer completed a single dose release just above 5.5 minutes with RESPULES and just above 5 minutes with a solution of the invention. In addition, pulsatile membrane nebulizers released a substantially higher percentage of corticosteroids in the FPF, which is generally defined as the fraction of particles smaller than 5 μ or the fraction of particles in cascade-impacting stages with a reduction of less than 6 μ. Consequently, the total nebulization time of the AERONEB GO is a quarter of the borri time for the Pari LC + air jet nebulizer. As a result, treatment time would be reduced with the pulsatile membrane nebulizer compared to the air jet nebulizer, and the amount of bude- monide emitted from the pulsatile membrane nebulizer is 2 to 3 times greater than the nebulizer. of air jet. The percentage of drug exiting the nebulizer (the emitted dose) was also determined to be 81% of the amount initially charged to the reservoir (the nominal dose). Therefore, less drug would need to be charged to the pulsed membrane nebulizer to treat the patient in need thereof to provide the same "patient dose" as provided by an air jet nebulizer.

Aerosol droplet size was determined using a Malvern Spraytec instrument. The pulsed membrane nebulizer Dv10, Dv50, and Dv90 are very similar to those for the reference product (PULMICORT RESPULES) and a CAPTISOL solution of the same concentration in an air jet nebulizer. This suggests that the formulation would be similarly distributed to the patient after inhalation.

A clinical study according to Example 17 was conducted to compare pulmonary deposition of budesonide from a radiolabelled liquid formulation and clearance of lung budesonide as determined by the appearance of budesonide in plasma. A solution formulation of the invention was compared to a suspension-based budesonide formulation. At various times up to 24 hours, plasma samples were collected and analyzed for budesonide and various pharmacokinetic parameters determined. The area under the plasma concentration time curve (AUC) is a measure of budesonide release to the lung, as oral absorption of corticosteroids was blocked by administration of charcoal. A comparison of AUC data was made by considering the dose delivered to each patient ("patient dose") or dose delivered to each patient's lungs ("lung dose") or dose delivered by the nebulizer or device (" emitted dose ") or dose available for nebulization or release (" nominal dose "or" nominal available dose "or" loaded dose "). AUC data (0-t, and 0- ~) were normalized in terms of budesonide (pg) released for each patient by dividing the AUC data by the corresponding dose for the patient. As used herein, the term "patient dose" is used to mean the amount of corticosteroid released to a patient following the completion of a nebulizer dosing cycle and is calculated by subtracting the sum of drug remaining in the nebulizer, drug removed from a patient's mouth, and the amount of exhalation filter collected from the amount of drug initially present in the nebulizer reservoir. The following expression can be used to calculate the patient dose (Ds): Ds = DriHic - (Dmw + Ddev), where Drinic denotes the amount of drug initially present in the nebulizer reservoir, Dmw denotes the amount of drug. removed from the mouth of a patient using a mouthwash. Ddev denotes the amount of drug remaining in the device following completion of an administration dosing cycle. The term Ddev includes the drug remaining in the reservoir upon completion of dosing, and the drug remaining in the remainder of the device upon completion of dosing. As used herein, the term "lung dose" is adopted to mean the amount of drug released into a patient's lungs, which amount is a "patient dose" subgroup. The dosage parameters used in this example are detailed below and are provided based on arithmetic methods.

<table> table see original document page 84 </column> </row> <table> <table> table see original document page 85 </column> </row> <table>

Pharmacokinetic data obtained from the study of Example 17 are summarized below. Data are presented in a geometric mean or individual patient base. The values given in the table below are based on the "dose to the patient".

<table> table see original document page 86 </column> </row> <table>

1TTS = Time to Spray. The percentage value can be used to calculate a nominal available dose for corticosteroid in the study conducted according to Example 17.

2 Using the added radioactive tracer, the dose of released budesonide can be calculated by extracting the amount of budesonide remaining in the nebulized after dose, exhalation filter, and mouthwash from the amount initially added to the nebulizer.

3The ranges in the table above are based on geometric means for a respective value as determined with each individual.

Based on the above data, the formulation of the invention provides a standard AUCt of 3 to 15 (or about at least 6) (pg * h / ml) / µg budesonide when about 60 to 65 µg budesonide has been released, a AUCt normalized from 7 to 11 (or about at least 8) (pg * h / ml) / µg budesonide when about 105 to 110 µg budesonides were released, and a normalized AUCt from 4 to 11 (or about of at least 7) (pg * h / ml) / pg budesonide when 165 to 170 æg budesonide were released based on the "patient dose". In addition, the formulation of the invention provided a standard AUCi of 4 to 16 (or about at least 8) (pg * h / ml) / pg budesonide when about 60 to 65 µg budesonide was released, a normalized AUCi of 8 to 12 (or about at least 10) (pg * h / ml) / µg budesonide when about 105 to 110 pg of budesonide were released, and a standardized AUCi of 5 to 16 (or about at least 10) (pg * h / ml) / æg budesonide when 165 to 170 æg of buesonide were released based on the "dose to the patient". The data are also summarized in FIG. 17, which is a plot of the "patient dose" geometric mean (pg budesonide) versus the geometric mean AUC (pg * h / ml), and FIG. 18, which is a plot of the geometric mean "lung dose" (æg budesonide) versus the geometric mean AUC (pg * h / ml).

In some embodiments, the invention includes a method of providing in a patient a normalized plasma AUCt for the patient's corticosteroid dose of at least 6 (pg * h / ml) / µg released corticosteroid, as a dose to the patient, comprising: administering to the patient by nebulization a unit dose comprising at least 45 µg, at least 48 µg, or 45 µg to 1000 µg, about 1 µg to 20 mg, about 1 µg to 10 µg. mg, 0.01 µg at 10 mg, 0.025 mg at 10 mg, 0.05 mg at 5 mg, 0.1 mg at 5 mg, 0.125 mg at 5 mg, 0.25 mg at 5 mg, 0.5 mg 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, or 0.5 mg to 2 mg corticosteroids dissolved in an aqueous liquid carrier comprising sulfoalkyl ether cyclodextrin.

FIGURE 19 is a "patient dose" plot (pg of bude-sonide) versus the corresponding AUC (pg * h / ml) for each individual patient of the study. The slope of the substantially linear solid line, taken from data through three different released doses, defines a dose response curve for a patient receiving the corticosteroid. As a result, tilt can be used to predict the dose a patient would need to provide a target plasma level in a second dose if the patient has received a first dose and the patient's AUC per pg of corticosteroid has been decreased. The inclination ranges from 5.7 to 16, or more specifically from 9 to 10, when data are observed on an individual patient basis.

The plasma concentration profile for budesonide for clinical study patients is depicted in FIGURE 20.

These normalized AUC data and associated radiorabel distribution data show that more of the patient's released dose into the lung and from there into the systemic circulation when budesonide was administered as a solution than when budesonide was administered as a suspension. Assuming that an equivalent dose deposited in the lung results in similar efficacy or systemic absorption, these results suggest that 1.6 to 5 times or 2 to 4 times less patient dose is required when administered in solution to be as effective when the reference suspension product. Depending on whether it is determined on an individual basis or a geometric mean basis, administration of a solution of the invention provides a 1.6-fold increase, 2.2-fold increase, 2.5-fold increase, a five-fold increase, a 1.6 to five-fold increase, a two to four-fold increase, a two to 3.5-fold increase, a two-to-three-fold increase, or at least one twice in AUCt or AUCi per pg of budesonide released compared to administration of the PULMICORT RESPULES suspension aqueous formulation. The AUCt or AUCi per μς of released budesonide was observed as variation per individual, with the value being greater than the above mentioned values for some individuals and lower than the above observed values for other individuals.

Data in the table below are based on the various different doses measured or determined during the study and summarize the enhancement level (factor) in the non-normalized or normalized pharmacokinetic profile parameter Cmax based on the nominal available dose, lung dose, donate to the patient, or dose delivered.

<table> table see original document page 89 </column> </row> <table> <table> table see original document page 90 </column> </row> <table>

According to the above table, the formulation and system of the invention can provide a Cmax (pg / ml) of 90 to 900, 200 to 600, 200 to 550, 200 to 250, 400 to 450, 500 to 600, 225 , 437, or 545 on a non-standard dose basis. The formulation and system of the invention may provide a Cmax standard dose (pg / ml / pg) of: 1) 0.3 to 2, 0.35 to 2, 0.6 to 1.5, 0.5 to 1.2 0.8 to 1, 0.8 to 0.9, 0.7 to 0.8, 0.4, 1.9, 0.6, 1.5, 0.5, 1.2, 0.35 , 0.7, 0.8, or 0.9 on a standard basis of nominal available dose; 2) 3.4 to 9.2, 3.5 to 8.5, 5.5 to 9.2, 4.5 to 7.5, 5.8 to 7, 3.4, 3.5, 4, 5, 5.5, 9.2, 8.5, 7.5, 5.8, 5.9, 6, or 7 on a standard lung dose basis; 3) 1.7 to 7.5, 3.2 to 4.1, 1.9 to 6, 3.2 to 7.5, 1.7 to 5.2, 3,6,4,1, 3,2, 1.9, 6, 3.2, 7.4, 7.5, 1.7, 5.2 or 5.3 on a normalized dose basis for the patient; 4) 0.9 to 3.3, 1.7 to 2.2, 0.9 to 3, 1 to 3, 1.7 to 3.3, 1 to 2.7, 1.9, 2.1, 2, 2, 1.7, 0.9, 1, 2, 3, 2.9, 3.2, 3.3 or 2.7 on a normalized emitted dose basis.

The solution of the invention provides an enhanced pharmacokinetic profile of the suspension based formulation. Based on the non-standard dose of corticosteroids, the Cmax provided by the corticosteroid solution is 1.6 to 2, 1.5 to 3, 1.5 to 2.5, 1.5 to 2, 1.5 , 1,6, 2, 2,5, or 3 times greater than the Cmax provided by the suspension-based formulation when the corticosteroid dose in solution and suspension is approximately the same amount loaded. Based on normalization to the nominal available corticosteroid dose, the Cmax provided by the corticosteroid solution is 1.8 to 6.2, 1.5 to 6.5, 2 to 6.5, 1.5 to 5 , 5, 2 to 4, 1.5 to 4, 1.5 to 3, 2.7, 3.3, 3.4, 1.5, 6.5, 2, 5.5, 4 or 3 times higher than the Cmax provided by the suspension based formulation. Based on normalization for lung corticosteroid dose, the Cmax provided by the corticosteroid solution is 1.4 to 4.3, 1.4 to 4.5, 1.5 to 4.5, 1.5 to 3.5, 1.5 to 3, 1.4 to 3, 1.5 to 2.5, 1.5 to 2, 2, 2.3, 1.4, 4.5, 3, 5, 3, 1.5 or 2.5 times higher than the Cmax provided by the suspension based formulation. Based on normalization for the patient's corticosteroid dose, the Cmax provided by the corticosteroid solution is 2 to 3.5, 2 to 5, 1.7 to 3.8, 1.7 to 5, 2, 7, 3, 2.4, 2, 3.5, 5, 1.7, or 3.8 times higher than the Cmax provided by the suspension-based formulation. Based on normalization of the dose of corticosteroid emitted, the Cmax provided by the corticosteroid solution is 1.9 to 6.3, 1.75 to 6.5, 2.2 to 4.2, 2.2 to 6.3 1.9 to 4.2, 3.2, 3.5, 3.6, 2.8, 1.75, 6.5, 2.2, 4.2, or 6.3 times higher than the Cmax provided by the suspension-based formulation.

Alternatively, the Cmax provided by the corticosteroid solution is at least 1.5, 1.6, 2, 2.6, and 3 times higher than the Cmax provided by the suspension-based formulation when the corticosteroid dose is costeroid in the solution is about 2 times lower than the suspension dose.

The data in the table below are based on the various different doses measured or determined during the study and summarize the enhancement level (factor) in the non-normalized or normalized AUCinf pharmacokinetic profile parameter based on the nominal available dose, lung dose, donate to the patient, or dose delivered. <table> table see original document page 92 </column> </row> <table> <table> table see original document page 93 </column> </row> <table> According to the table above, the formulation and The inventive system can provide an AUCinf (pg * h / ml) of 500 to 1700, 530 to 1650, 250 to 2500, 280 to 1300, 780 to 1300, 980 to 2450, 275, 775, 980, 2400, 2500 , 1300, 1290, 530, 1650, 250, 280 or 780 on a non-standard dose basis. The formulation and system of the invention may provide a standardized dose (pg / ml / pg) AUCint of: 1) 1 to 5.5, 2 to 2.2, 1 to 5.3, 1.1 to 5, 2, 1.5 to 2.6, 1.3 to 3.3, 2, 2.1, 2.2, 1, 5.5, 5.3, 5.2, 1.5, 2.6, 1.3 or 3.3 on a standard basis of nominal available dose; 2) 10 to 25, 14 to 18, 10.2 to 20, 13.6 to 18.8, 11.2 to 24.7, 10.2, 20, 13.6, 14, 19, 18.8, 11, 11.2, 25, 24.7, 14.2, 16.2, 17.3 on a normalized dose basis for the lung; 3) 4 to 16, 4.2 to 16.1, 8 to 12.2, 5.4 to 16, 5.4 to 17, 8.5 to 9.6, 8.5, 9.5, 9, 6, 4.2, 16.1, 8, 12.2, 12, 5.4, 16, 17, or 16.5 on a normalized dose basis for the patient; 4) 2.5 to 9, 2.6 to 8.5, 4.5 to 5.1, 2.5 to 8, 2.6 to 7.9, 4.2 to 6.7, 3.1 to 8.5, 3.2 to 8.5, 4.5, 4.6, 5, 5.1, 2.5, 2.6, 4.2, 3.1, 9, 8.5, 5, 1, 8, 7.9, or 6.7 on a normalized emitted dose basis.

Accordingly, the solution of the invention provides an enhancing pharmacokinetic profile of the suspension based formulation. Based on the non-standard dose of corticosteroids, the AUCinf provided by the corticosteroid solution is 1.6 to 2.5, 1.6 to 3.1, 1.5 to 3.5, 1.5 to 3.3, 2, 5 to 3.3, 3.1, 1.5, 3.3, 1.6, or 2.5 times higher than the AUCinf provided by the suspension-based formulation when the foricosteroid dose in solution and suspension is about the same. Based on the standardization for the nominal available corticosteroid dose, the AUCint provided by the corticosteroid solution is 1.75 to 6.5, 1.75 to 6.1, 2 to 6.5, 2 to 6.1, 2 to 4.5, 2 to 4.4, 3.3, 3.2, 3.5, 3.4, 1.75, 6.5, 6.1, 2, 4.5, or 4.4 times higher than the AUCint provided by the suspension based formulation. Based on normalization for the corticosteroid dose to the lung, the AUCint provided by the corticosteroid solution is 1.2 to 3.5, 1.2 to 4, 1.2 to 3, 1.2 to 2.85. 1.5 to 3.5, 1.4 to 3.5, 2, 2.2, 2.3, 2.4, 1.2, 3, 4, 2.85, 1.5, 3.5 , or 1.4 times higher than the AUCinf provided by the suspension-based formulation. Based on normalization for the patient's corticosteroid dose, the AUQnt provided by the corticosteroid solution is 1.6 to 4.9, 1.5 to 5, 1.6 to 5, 1.6 to 3.7. , 1.6 to 3.6, 2 to 4.9, 1.9 to 4, 2.6, 1.5, 5, 1.6, 3.7, 3.6, 2, 4.9, 1 , 9, or 4 times higher than the AUCinf provided by the suspension-based formulation. Based on the normalization for Corticosteroid Issued Dose, the AUCinf provided by the corticosteroid solution is 1.5 to 6, 1.7 to 6, 1.9 to 6, 1.9 to 5.4, 2.3 at 5.8, 1.9 to 5.5, 1.9 to 5.8, 1.5, 6, 1.7, 1.9, 5.4, 2.3, 5.8, 5.8 , 3.2, 3.5, or 3.6 times higher than the AUCinf provided by the suspension-based formulation.

Alternatively, the AUCinf provided by the corticosteroid solution is at least 1.5, 1.6, 2, 2.5, 3, and 3.1 times higher than the AUCinf provided by the suspension-based formulation when corticosteroid dose in the solution is about 2 times lower than the suspension dose.

The data in the table below are based on the various different doses measured or determined during the study and summarize the enhancement level (factor) in the non-normalized or normalized pharmacokinetic profile parameter based on the nominal available dose, lung dose, dose to the patient, or dose emitted.

<table> table see original document page 95 </column> </row> <table> 2 <table> table see original document page 96 </column> </row> <table>

A determination of dose distribution in subjects (Example 17) was made to determine the efficiency of dose deposition to the lungs. Results are detailed in the table below and in FIG. 22

<table> table see original document page 96 </column> </row> <table> <table> table see original document page 97 </column> </row> <table>

1 (A) Spray misted Budesonide suspension - 100% TTS (spray time)

2 (B) Captisol-Enabled® Budesonide Formulation - 25% TTS

3 (C) Captisol-Enabled® Budesonide Formulation - 50% TTS

4 (D) Captisol-Enabled® Budesonide Formulation - 75% TTS

The data demonstrate that administration of the inventive solution resulted in lower oropharyngeal corticosteroid deposition compared to administration of the control suspension formulation. In addition, the formulation provided at least 20% to 85%, or 30% to 80%, or at least 30%, at least 40%, at least 56%, at least 59%, at least 62% by weight of deposition. corticosteroid therapy based on the dose delivered. The percentage of lung deposition may also be increased by employing a nebulizer capable of providing a larger breathable fraction and smaller MMAD for the nebulized mist. Suitable nebulizers are ultrasonic, vibrating mesh, vibrating cone, vibrating plate nebulizers or those that expel a liquid formulation through a self-retaining nozzle arrangement. For example, Aradigm AERx pulmonary release systems, AERx Essence and AERx Ultra, are particularly suitable for use according to the invention, as is recognized in the art when providing dose controlled expression, aerosol particle size control. generated, inhaled aerosol particle size control, and inhalation control and release process (Farr et al., Drug Delivery Technology, May 2002, Vol. 2, No. 3, 42-44). For example, the PARI eFlow vibratory plate nebulizer is particularly available for use in accordance with the invention, as is recognized in the art when providing the above mentioned desired performance parameters (Keller et al. (ATS 99, h International Conference , Seattle, May 16-21, 2003; poster 2727).

Because of the improved systemic bioavailability of a corticosteroid released into the lungs by pulmonary administration according to the invention, the composition or formulation of the invention will provide an improved therapeutic benefit or improved clinical benefit over an equivalent dose of corticosteroid administered as an aqueous suspension. .

Example 30 details a study conducted on dogs in which a budesonide solution of the invention and a reference formulation (PULMICORT RESPULES suspension) were administered by nebulization with a Pari LC air jet nebulizer. The results shown in FIG. 21 demonstrate an average budesonide plasma level as a function of time. The AUCo-8hr of the solution formulation was 1.9 times higher than the reference suspension formulation. The solution formulation also emitted 1.23 times as much budesonide as the reference formulation over the same time period. Detailed results are also provided in the table below.

<table> table see original document page 98 </column> </row> <table> <table> table see original document page 99 </column> </row> <table>

According to the table above, the formulation and system of the invention may provide an AUC0-S hours (pg * h / ml) from 2000 to 3000, 2500 to 2700. 2000, 3000, or 2600 on a non-standard dose basis. The formulation and system of the invention may provide a standard dose AUCinf (pg / ml æg) of: 1) 2 to 3, 2.5 to 2.7, or 2.6 on a standard nominal loaded dose basis. ; 2) 3 to 4, 3.4 to 3.5, or 3.4 on a normalized emitted dose basis.

The formulation, system and method of the invention provided greater AUC0-Shoras than the suspension-based formulation of PULMICORT RESPULES. Based on the standardized (loaded) nominal corticosteroid dose, the AUC0.8hr provided by the corticosteroid solution is at least 1.7, 1.8, 1.9, or 2 times higher than the AUC0-8 hours supplied. by the suspension-based formulation when the corticosteroid dose in the solution and suspension is approximately the same. Based on normalization for Corticosteroid Issued Dose, the AUC0.8 hours provided by the corticosteroid solution is at least 1.5, 1.6, 2 times higher than the AUC0.8hr provided by the suspension-based formulation. .

According to the table above, the inventive formulation and system may provide a Cmax (pg / ml) of 1600 to 1800, 1650 to 1750, or 1700 on a non-standard dose basis. The formulation and system of the invention may provide a normalized dose Cmax (pg / ml / µg) of 1) 1 to 2, 1.6 to 1.8, or 1.7 on a nominally loaded nominal dose normalized basis; 2) 2 to 2.5, or 2.2 on a standard basis of emitted dose.

The formulation, system and method of the invention provided a larger CMA than the suspension-based formulation of PULMICORT RESPULES. Based on the normalized (loaded) nominal dose of corticosteroid, the Cmax provided by the corticosteroid solution is at least 1.7, 1.8, 1.9, or 2 times higher than the Cmax provided by the corticosteroid formulation. suspension when the corticosteroid dose in the solution and suspension is approximately the same. Based on normalization to the emitted dose of corticosteroids, the Cmax provided by the corticosteroid solution is at least 1.5, 1.6, 2 times higher than the Cmax provided by the suspension-based formulation.

In some aspects, the method and dosage form of the invention thus provides an improved method of administering a corticosteroid suspension-based unit dose, the method comprising the step of adding a sufficient amount of SAE-CD to convert the suspension into a clear solution and then administer the clear solution to a patient. As a result, the method of the invention provides increased total corticosteroid release as well as increased rate of administration compared to the initial unit dose suspension formulation.

Included data can also be used to estimate the percentage of emitted or released corticosteroid dc that is absorbed into a patient's bloodstream. In some embodiments, more than 20%, more than 25%, more than 29%, more than 35% of the Issued Dose may be absorbed into the patient's bloodstream. In some modalities, more than 40%, more than 50%, more than 55% of patient pain can be absorbed into the patient's bloodstream. In some modalities, more than 10%, more than 12%, more than 15% of the nominal available dose may be absorbed into the patient's bloodstream.

Corticosteroids that are useful in the present invention generally include any steroid produced by the adrenal cortex, including glucocorticoids and mineralocorticoids, and naturally occurring synthetic analogues and corticosteroid derivatives having anti-inflammatory activity. Suitable synthetic analogues include prodrugs, ester derivatives. Examples of corticosteroids that may be used in the compositions of the invention include aldosterone, beclometastone, betamethasone, budesonide, ciclesonide (Altana Pharma AG), cloprednol, cortisone, cortivazole, deoxycortone, desonide, deoxymethasone, dexamethasone, difluorcortolone, fluclorolone, flumetasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorcortisone, fluorcortolone, fluormetolone, flurandrenolone, flutcinone hydrocortisone, icometasone, meprednisone, methylprednisone, mometasone, parametasone, prednisolone, prednisone, roylleponide, RPR 106541, thixocortol, triamcinolone, and their pharmaceutically acceptable derivatives, such as such as beclomethasone dipropionate (anhydrous or monohydrate), beclomethasone monopropionate, dexamethasone 21-isonicotinate, fluticasone propionate, icomethasone inlay, tix 21-pivalate ocortol, and the accepted triamcinolone. Particularly preferred are compounds such as beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. Other corticosteroids not yet marketed, but which will be marketed subsequent to the filing of this patent application, are considered useful in the present invention unless otherwise experimentally established that they are not suitable.

Corticosteroids can be grouped according to their relative lipophilicity as described by Barnes et al. (Am. J. Respir. Care Med. (1998), 157, p. S1-S53), Miller-Larsson et al. (Am J. Respir Care Med. (2003), 167, A773), DE Mager et al. (J. Pharm. Sci. (Nov. 2002), 91 (11), 2441-2451) or S. Edsbacker (Uptake, Retention, and Biotransformation of Corticosteroids in the Iung and Airways. In: Schleimer RP , O'Byrne PMO, Szefler SJ, Brattsand R., editor (s) Inhaled steroids in asthma: optimizing effects in the airways New York: Mareei Dekker, 2002: 213 - 246). Generally, the less lipophilic a corticosteroid is, the lower the amount of SAE-CD required to dissolve it in an aqueous medium and vice versa. Corticosteroids that are less lipophilic than flunisolid generally require a molar ratio of SAE-CD to corticosteroids of less than 10: 1 to dissolve corticosteroids in an aqueous medium. Exemplary corticosteroids in this group include hydrocortisone, prednisolone, prednisone, dexamethasone, betamethasone, methylprednisolone, triamcinolone, and fluocortolone. Some embodiments of the invention exclude corticosteroids that are less lipophilic than uunisolid.

Corticosteroids that are at least as lipophilic as or more lipophilic than flunisolid generally require a SAE-CD to corticosteroid molar ratio of more than 10: 1 to dissolve the corticosteroid in an aqueous medium. In some embodiments, the corticosteroid using the invention is at least as lipophilic as or more lipophilic than flunisolid. Exemplary corticosteroids in this group include beclomethasone, beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyryl ciclesonide, flunisolide, fluticasone, fluticasone propionate, mometasone, mometasone furoate, triamcinolone acetonide.

The suitability of a corticosteroid for use in the inhalable liquid composition / formulation can be determined by performing a phase solubility binding study as detailed in Example 23. Phase solubility binding data is used to determine saturated solubility. of a corticosteroid in the presence of varying amounts of SAE-CD in an aqueous liquid vehicle. The phase solubility binding curve shown in FIG. 3 demonstrates the saturated solubility of budesonide in an aqueous liquid carrier comprising γ-CD, ΗΡ-β-CD or SBE7-p-CD. A phase solubility curve in the graph defines the limit for saturated corticosteroid solubility in solutions containing several different concentrations of cyclodextrin. A molar phase solubility curve can be used to determine the molar ratio of SAE-CD to corticosteroid or corticosteroid to SAE-CD at various corticosteroid concentrations. The area below the phase solubility curve, for example, of FIG. 3, denotes the region where the corticosteroid is solubilized in an aqueous liquid medium to provide a substantially clear aqueous solution. In this region, SAE-CD is present in excess molar corticosteroid in an amount sufficient to solubilize the corticosteroid present in the liquid vehicle. The boundary defined by the phase solubility curve will vary according to the corticosteroid and SAE-CD within a composition or formulation of the invention. The Table below provides a summary of the minimum SAE-CD to corticosteroid molar ratio required to obtain saturated corticosteroid solubility in the composition or formulation of the invention under the conditions studied.

<table> table see original document page 103 </column> </row> <table>

* This value was determined in the presence of SAE-CD under the conditions detailed in Examples 18, 23 following the solubility values given in the preceding and following text. Saturated solubility of a corticosteroid in the presence of a fixed amount of SAE-CD will vary according to corticosteroid identity and SAE-CD. The Table below summarizes some solubility data for the corticosteroids listed in the absence (intrinsic corticosteroid solubility in the aqueous test medium) and in the presence of two different SAE-CD's as determined herein.

<table> table see original document page 104 </column> </row> <table>

The above data may be used in combination with the phase solubility data to prepare formulations according to the invention having a target corticosteroid and SAE-CD concentration. Accordingly, some embodiments of the invention comprise a corticosteroid having an intrinsic solubility in water approaching or less than the intrinsic solubility of flunisolid (less than about 11 x 10-5 M or less than about 11, 3 x 10 "5 M) in water as determined herein.

Although a composition or formulation of the invention may comprise the corticosteroid present in an aqueous medium at a concentration to its saturated solubility in the presence of a particular concentration of SAE-CD1, some embodiments of the invention include those wherein the corticosteroid is present in a concentration. concentration that is lower than its solubility saura in the presence of that SAE-CD concentration. Corticosteroid may be present at a concentration that is 95% or less, 90% or less, 85% or less, 80% or less, or 50% or less of its saturated solubility as determined in the presence of SAE-CD. It is generally easier to prepare solutions that comprise corticosteroids at a concentration that is less than their saturated solubility in the presence of SAE-CD.

Therefore, the molar ratio of SAE-CD to corticosteroid in a formulation or composition of the invention may exceed the molar ratio obtained in the saturated solubility of corticosteroid in the presence of SAE-CD, as defined by the phase-to-phase solubility binding curve. the corticosteroid. In such a case, the molar ratio of SAE-CD to corticosteroid in the composition or formulation will be at least 1%, at least 2%, at least 5%, at least 7.5%, at least 10%. , at least 15%, at least 20%, at least 25%, at least 50%, at least 75%, at least 100%, or at least 200% greater than the molar proportion in corticosteroid saturated solubility in the presence of SAE-CD. For example, if the molar ratio in saturated solubility is about 14: 1, then the molar ratio in the composition or formulation may be at least 14.1: 1 (for at least 1% higher), at least 14.3: 1. (at least 2% higher), at least 14.7: 1 (for at least 5% higher), at least 15.4: 1 (for at least 10% higher), at least 16.1: 1 (for at least 15% higher), at least 16.8: 1 (for at least 20% higher), at least 17.5: 1 (for at least 25% higher), at least 21: 1 (for at least 50% higher) at least 24.5: 1 (for at least 75% higher), at least 28: 1 (for at least 100% higher), or at least 42: 1 (for at least 100% higher).

Changes in a molar ratio of SAE-CD to corticosteroids can impact the total output of a nebulizer. A study was conducted using the PARI LC PLUS air jet nebulizer and solutions containing varying amounts of SAE-CD in 2 ml of 250 μς / ιτιΙ of PULMICORT RESPULES. Each preparation was nebulized until no more sustained steam was visibly emitted. At the end of each activation, the amount of budesonide remaining in the nebulizer reservoir was determined. The SAE-CD to corticosteroid molar ratios used were 10: 1, 14: 1, and 20: 1. The data indicate that the increase in molar ratio resulted in an increase in the amount of budesonide released and a decrease in the amount of budesonide remaining in the reservoir.

Changes in a molar ratio of SAE-CD to corticosteroids may also have an impact on the dissolution rate of corticosteroids in an aqueous medium. A study was conducted on a drum mixer, having containers with solutions containing varying amounts of SAE-CDj eg CAPTISOL, and a fixed amount of fluticasone propionate or mometasone furoate. Samples were prepared by mixing the corticosteroid with a solution containing SAE-CD in a centrifuge for about 30 seconds, and then placing the containers in the cylinder mixer. Aliquots were taken periodically from each container and the amount of dissolved corticosteroid was determined. The SAE-CD to corticosteroid molar ratios used were 10: 1, 14: 1, and 20: 1. The data indicate that the increase in molar ratio resulted in an increase in corticosteroid dissolution rate.

The corticosteroid compound is present in the final diluted corticosteroid composition designed for inhalation in an amount from about 1 μg / ml to about 10 mg / ml, about 10 μg / ml to about 1 mg / ml, or about 20 Mg / ml to about 500 µg / ml. For example, the drug concentration may be between about 30 and 1000 μg / ml for acetonide triamcino- phate, and between about 50 and 2000 μρ / ιηΙ for budesonide, depending on the volume to be administered. Following the preferred methods of the present invention, relatively high concentrations of corticosteroid can be obtained in an aqueous based composition.

Similarly, the corticosteroid compound is present in the final diluted corticosteroid composition designed for nasal administration in an amount from about 10 μg / ml to about 6 μg / ml, 50 μg / ml to about 10 mg / ml. ml, about 100 μg / ml to about 2 mg / ml, or about 300 μg / ml to about 1 mg / ml. For example, the drug concentration is between about 250 μg / ml to 1 mg / ml or 250 μg / ml to 6 mg / ml for triamcinolone acetonide, and about 400 μg / ml to 1.6 mg / ml or 250 μg / ml and 6 mg / ml for budesonide, depending on the volume to be administered.

For the treatment of pulmonary and bell-related disorders, the diluted corticosteroid composition is prepared as described herein. The corticosteroid for such treatment is preferably beclomethasone dipropionate, betamethasone, budesonide, dexamethasone, flunisolide, fluticasone propionate, mometasone furoate, or triamcinolone acetonide, and is formulated at the concentrations described below. . The daily dose of corticosteroid is usually about 0.05 to 10 mg, depending on the drug and the disease, according to the Physician's Desk Reference (PDR). However, in view of the improved bioavailability of a corticosteroid when administered as a solution of the invention, the dose required to achieve a desired clinical goal, clinical benefit, or therapeutic benefit may be less than the corresponding dose indicated in PDR.

The unit dose of budesonide can also be administered once a day, once every two days, once a week, once a month, or even less frequently as mentioned in United States Patents Nos. 6,598,603 and 6,899,099. wherein a dose comprises 0.05 to 2.0 mg or 0.25 to 1.0 mg budesonide. Administration may be during the day and / or at night. One budesonide, or corticosteroid, can be administered twice a day, three or more times a day, or on an as needed basis.

In some embodiments, the dose comprises 1 μg at 20 mg, 0.01 mg at 10 mg, 0.025 mg at 10 mg, 0.05 mg at 5 mg, 0.1 mg at 5 mg, 0.125 mg at 5 mg, 0 , 25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg, 1 μg, 10 μg, 25 μg, 50 μg, 100 μg, 125 μ9, 200 250 μg, 25 to 66 μg, 48 to 81 μg, 73 to 125 μg, 40 μg, 64 μg, 95 μg, 35 95 μg, 25 to 125 μg, 60 to 170 μg, 110 μg, 170 μg, 45 to 220 μg, 45 to 85 μg, 48 to 82 μg, 85 to 160 μg, 140 to 220 μg, 120 to 325 μg) 205 μg, 320 μg, 325 μg, 90 to 400 μg, 95 to 170 μg, 165 to 275 μg, or 275 to 400 μg budesonide, said dose being a nominal dose, nominal available dose, emitted dose, released, dose to patient, or dose to lung.

Corticosteroids may be present in their neutral, tonic, salt, basic, acidic, natural, synthetic, diastereoisomeric, isomeric, enantiomerically pure, racemic, solvate, anhydrous, hydrate, chelate, derivative, analogous, esterified, non-esterified, or otherwise common. Whenever an active agent is mentioned here, all such available forms are included. For example, all known forms of budesonide are considered to be within the scope of the invention.

The formulation of the invention may be used to deliver two or more different active agents. Particular combinations of active agents may be provided by the present formulation. Some combinations of active agents include: 1) a first drug of a first therapeutic class and a different second drug of the same therapeutic class; 2) a first drug of a first therapeutic class and a different second drug of a different therapeutic class; 3) a first drug having a first type of biological activity and a different second drug having approximately the same biological activity; 4) a first drug having a first type of biological activity and a different second drug having a second different type of biological activity. Illustrative combinations of active agents are described herein.

A corticosteroid, such as budesonide, may be administered in combination with one or more drugs. Such other drugs include: B2 adrenoreceptor agonist, topical anesthetic, D2 receptor agonist, anticholinergic agent. B2-adrenoreceptor agonists for use in combination with the compositions provided herein include, but are not limited to, Albuterol (alpha1 - (((1,1-dimethylethyl) amino) methyl) -4-hydroxy-1,3 benzene dimethanol); Bambuterol (5- (2 - ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-phenylene ester of dimethyl carbamic acid); Bitolterol (4- (2 - ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,2-phenylene ester of 4-methylbenzoic acid); Broxaterol (3-bromo-alpha - (((1,1-dimethylethyl) amino) methyl) -5-isoxazolmethanol); Isoproterenol (4- (1-hydroxy-2 - ((1-methylethyl) amino) ethyl) -1,2-benzene diol); Trimethoquinol (1,2,3,4-tetrahydro-1 - ((3,4,5,5-trimethoxyphenyl) methyl) -6,7-isoquinolinadiol); Clenbuterol (4-amino-3,5-dichloro-alpha - (((1,1-dimethylethyl) amino) methyl) benzenomethanol); Fe-noterol (5- (1-hydroxy-2 - ((2- (4-hydroxyphenyl) -1-methylethyl) amino) ethyl) -1,3-benzenodiol); Formoterol (2-hydroxy-5 - ((1 RS) -1-hydroxy-2 - (((1 RS) -2- (p-methoxyphenyl) -1-methylethyl) amino) ethyl) formanilide); (R1R) -FormoteroI; Deformoterol ((R, R) or (S, S) -3-amino-4-hydroxy-alpha ((((2- (4-methoxyphenyl) -1-methyl-ethyl) amino) methyl) benzenomethanol); Hexoprenaline (4,4 '- (1,6-hexane-diyl) -bis (imino (1-hydroxy-2,1-ethanediyl))) bis-1,2-benzenediol); Isoetarin (4- (1-hydroxy-2 - ((1-methylethyl) amino) butyl) -1,2-benzenediol); Isoprenaline (4- (1-hydroxy-2 - ((1-methylethyl) amino) ethyl) -1,2-benzenediol); Metaprerenol (5- (1-hydroxy-2 - ((1-methylethyl) amino) ethyl) -1,3-benzenediol); Picumeterol (4-amino-3,5-dichloro-alpha - (((6- (2- (2-pyridinyl) ethoxy) hexyl) amino) methyl) benzenomethanol); Pyrbuterol (α alpha 6 - (((1,1-dimethylethyl) amino) methyl) -3-hydroxy-2,6-pyridinemethanol); Procaterol (((R *, S *) - (±) -8-hydroxy-5- (1-hydroxy-2 - ((1-methylethyl) amino-) butyl) -2 (1H) -quinolinone); ((7- (3 - ((2- (3,5-dihydroxyphenyl) -2-hydroxyethyl) amino) propyl) -3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione Rimiterol (4- (hydroxy-2-piperidinylmethyl) -1,2-benzenediol); Salbutamol ((±) -alpha1 - (((1,1-dimethylethyl) amino) methyl) -4-hydroxy-1,3 (R) -SaIbutamol; Salmeterol ((±) -4-hydroxy-alpha 1 - (((6- (4-phenylbutoxy) hexyl) -amino) methyl) -1,3-benzenedimethanol (R) -SaImethyl; terbutaline (5- (2 - ((1,1-dimethylethyl) amino) -1-hydroxyethyl) -1,3-benzenediol); Tulobuterol (2-chloro-alpha) - (( (1,1-dimethylethyl) amino) methyl) benzenomethanol), and TA-2005 (8-hydroxy-5 - ((1 R) -1-hydroxy-2- (N - ((1 R) -2- (4-methoxyphenyl) -1-methylethyl) amino) ethyl) carbostyryl).

Dopamine (D2) receptor agonists include, but are not limited to, apomorphine ((r) -5,6,6a, 7-tetrahydro-6-methyl-4H-dibenzo [de, g] quinoline-10,11 -diol); Bromocriptine ((5 .alpha.) -2-bromo-12'-hydroxy-2 '- (1-methylethyl) -5' - (2-methylpropyl) ergotaman-3 ', 6'> 18-trione) ; Cabergoline ((8.beta.) -N- (3- (dimethylamino) propyl) -N - ((ethylamino) carbonyl) -6- (2-propenyl) ergoline-8-carboxamide); Lysuride (N '- ((8-alpha -) - 9,10-didehydro-6-methylergolin-8-yl) -N, N-diethylurea); Pergolide ((8-beta -) - 8 - ((methylthio) methyl) -6-propylergoline); Levodopa (3-hydroxy-L-tyrosine); Pramipexole (s) -4,5,6,7-tetrahydro-N 6 -propyl-2,6-benzothiazoldiamine); Quimpirol Hydrochloride (trans - (-) - 4aR-4,4a, 5,6,7, 8,8a, 9-octahydro-5-propyl-1H-pyrazolo [3,4-g] quinoline) hydrochloride; Ropinirole (4- (2- (dipropylamino) ethyl) -1,3-dihydro-2H-indol-2-one); and Talipexole (5,6,7,8-tetrahydro-6- (2-propenyl) -4H-thiazolo [4,5-d] azepin-2-amine). The other D2 receptor agonists for use herein are described in International Patent Application Publication No. WO 99/36095, the relevant disclosure of which is hereby incorporated by reference.

Anticholinergic agents for use herein include, but are not limited to, ipratropium bromide, oxitropium bromide, atropine methyl nitrate, atropine sulfate, ipratropium, belladone extract, scopolinamine, scopolamine metobromide, homatropine metobromide, hioscia - mine, isopriopramide, orphenadrine, benzalkonium chloride, tiotropium bromide and glycopyrronium bromide. In certain embodiments, the compositions contain an anticholinergic agent, such as ipratropium bromide or tiotropium bromide, at a concentration of about 5 μg / mL to about 5 mg / mL, or about 50 μg. / mL to about 200 µg / mL. In other embodiments, the compositions for use in the methods included herein contain an anticholinergic agent, including ipratropium bromide and tiotropium bromide, at a concentration of about 83 μg / mL or about 167 μg / mL.

Other active ingredients for use herein in combination therapy include, but are not limited to, IL-5 inhibitors, such as those described in United States Patent Nos. 5,668,100, N2 5,683,983, N 2 No. 5,677,280, No. 6,071,910 and No. 5,654,276, the relevant descriptions of which are hereby incorporated by reference; antisense modulators of IL-5, such as those described in U.S. Patent No. 6,136,603, the relevant disclosure of which is hereby incorporated by reference; millinone (1,6-dihydro-2-methyl-6-oxo- [3,4'-bipyridine] -5-carbonitrile); Millenone Iactate; tryptase inhibitors, such as those described in U.S. Patent No. 5,525,623, the relevant disclosure of which is hereby incorporated by reference; tachykinin receptor antagonists such as those described in U.S. Patent Nos. 5,691,336, No. 5,877,191, No. 5,929,094, No. 5,750,549 and No. 5,780,467, the relevant descriptions of which are hereby incorporated by reference; leukotriene receptor antagonists such as sodium montelukast (Singular®, R- (E) -1 - [[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl-] phenyl] - 3- [2- (1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropanoacetic acid monosodium), 5-lipoxygenase inhibitors such as zileuton (Zyflo®, Abbott Laboratories, Abbott Park, III .), and anti-IgE antibodies, such as Xolair® (recombinant humanized anti-IgE monoclonal antibody (CGP 51901; IGE 025A; rhuMAb-E25), Genentech, Inc., South San Francisco, California), and anesthetics such as lidocaine, N-arylamide, aminoalkyl benzoate, prilocaine, etidocaine (United States Patent Nos. 5,510,339, No. 5,631,267, and No. 5,837,713, the relevant descriptions of which are, hereby incorporated by reference).

Illustrative combination formulations of the invention comprise the following components.

<table> table see original document page 111 </column> </row> <table>

A formulation comprising a corticosteroid and other active ingredient may be prepared according to the examples below.

In one embodiment, SAE-CD is present in an amount sufficient to solubilize the corticosteroid and other active ingredient. In another instance, SAE-CD is present in an amount sufficient to solubilize the corticosteroid or other active ingredient. Depending on the other active ingredient used, it may or may not competitively bind against the corticosteroid with SAE-CD. In some embodiments, SAE-CD has a greater equilibrium binding constant for the other active ingredient than it has for corticosteroids. In some embodiments, SAE-CD has a higher balance binding constant for corticosteroids than it has for the other active ingredient. In some embodiments, SAE-CD has approximately the same equilibrium binding constant for the other active ingredient as it does for corticosteroids. Alternatively, the other active ingredient does not bind to SAE-CD even if the corticosteroid binds. Accordingly, the invention provides embodiments in which SAE-CD solubilizes corticosteroid, the other active ingredient, or a combination thereof. The invention also provides embodiments in which SAE-CD solubilizes at least a larger portion of the corticosteroid, other active ingredient, or each. The invention also provides embodiments in which SAE-CD does not solve the other active ingredient.

The molar ratio of SAE-CD to corticosteroid and SAE-CD to another active ingredient may vary as needed to provide a combination formulation as described herein. SAE-CD is usually present in molar excess over corticosteroids, the other active ingredient, or both.

The phase solubility binding curve for salmeterol and budesonide xinafoate was determined as described herein, and the approximate equilibrium binding constant (Ki) of each with CAPTISOL was determined. The approximate Ki for salmeterol xinafoate was approximately 3,500, and the approximate Ki for budesonide was 600 under the test conditions used. The molar ratio of CAPTISOL to salmeterol sinafoate in saturated solubility was about 3.2 under the test conditions used. It may be a reduction in the amount of budesonide soluble by CAPTISOL in the presence of salmeterol xinafoate; however, clear aqueous liquid solution formulations comprising therapeutically effective amounts of budesonide and salmeterol xinafoate have been used.

The formulation comprising budesonide, albuterol and SAE-CD was prepared according to Example 25. The formulation became clear after preparation. The combination of budesonide and albuterol has been shown to be physically and chemically stable and would be expected to provide the same improved aerosol performance and AUC per dosed budesonide as the budesonide solution alone. In addition, the patient would benefit from the simultaneous administration of both drugs.

The invention includes methods for treating, preventing, or ameliorating one or more symptoms of a corticosteroid responsive disorder, an airway disorder or disorder, for example, respiratory or pulmonary disorders such as bronchoconstrictive disorders; bell disorders such as sinusitis. The method also includes administering one or more of (a), (b), (c) or (d) as follows: (a) a P2-adrenoreceptor agonist; (b) a dopamine receptor (D2) agonist; (c) a prolifatic therapeutic substance, such as a steroid; or (d) an anticholinergic agent; concurrently with, prior to or subsequent to, the composition provided herein.

Embodiments of the present invention allow combinations to be prepared in a variety of ways:

1) Mixing ready-to-use solutions of a β2 agonist such as levalbuterol or anticholinergic such as ipatropium bromide with a ready-to-use corticosteroid solution on SAE-CD;

2) Mixing ready-to-use solutions of a β2 agonist or anticholinergic with a concentrated solution of a dissolved corticosteroid using SAE-CD;

3) Mixing a ready-to-use solution of a β2 agonist or anticholinergic with substantially dry SAE-CD and a substantially dry corticosteroid;

4) Mixing a ready-to-use solution of a β2 agonist or anticholinergic agonist with a substantially dry mixture of SAE-CD and a corticosteroid or, more conveniently, a premeasured amount of the mixture in a unit container such as a capsule (pour into one capsule in solution ready for use);

5) Mixing a ready-to-use solution of a corticosteroid, such as budesonide, with a substantially dry, long acting or short acting β2 agonist and / or a substantially dry anticholinergic such as ipatropium bromide or tiotropium bromide;

6) Dissolving a substantially dry β2 agonist, and / or a substantially dry anticholinergic and a substantially dry SAE-CD plus a substantially dry corticosteroid.

The materials used herein may be used in micronized or non-micronized form and crystalline, polymorphic or amorphous form. This is particularly true of corticosteroids and other active ingredients.

It is well understood by those skilled in the art that the aforementioned solutions or powders may optionally contain other ingredients such as buffers and / or agents for adjusting tonicity and / or antimicrobials and / or additives or other such excipients. as described herein or as currently used in inhalable liquid formulations to improve nebulizer outlet.

The dosage, use and administration of the therapeutic agents described herein are generally intended to follow the guidelines given in the Physician's Desk Reference, 55th Edition (Thompson Healthcare, Montvale, NJ, 2005), the relevant description of which is, hereby incorporated by reference.

Bronchoconstrictor disorder to be treated, prevented, or whose symptoms should be ameliorated is associated with asthma, including but not limited to bronchial asthma, allergic asthma, and intrinsic asthma, for example, late asthma. and airway hypersensitivity; and particularly in modalities where an anticholinergic agent is used, other chronic obstructive pulmonary diseases (COPDs), including but not limited to chronic bronchitis, emphysema, and associated cor pulmonale (heart disease secondary to lung and system disease). with pulmonary hypertension, right ventricular hypertrophy and right heart failure. COPD is often associated with cigarette smoke, infections, environmental pollution and exposure to occupational dust.

The formulation according to the invention will have a shelf life of no less than 6 months. In this case, shelf life is determined only in relation to the increase in the amount of budesonide degradation by-products or the reduction in the amount of budesonide that remains in the formulation. For example, for a formulation having a shelf life of at least six months, the formulation will not demonstrate an unacceptable and substantial increase in the amount of degradants during the storage period of at least six months. Criteria for acceptable shelf life are established as required according to a given product and its storage stability requirements. In other words, the amount of degradants in a formulation having an acceptable shelf life will not increase beyond a predetermined value during the intended storage period. On the other hand, the amount of degradants of a formulation having an unacceptable shelf life will increase beyond the predetermined value during the intended storage period.

The method of Example 3 was followed to determine the stability of budesonide in solution. Shelf life was defined as the time to 10% power loss. Under the conditions tested, the power loss was first order. The shelf life of a CaptisoI-EnabIecF Budesonide Inhalation Solution (a solution comprising budesonide and SBE7-P-CD) is more than about 3 years at a pH between 4 and 5, ie about 90 months at pH 4.0 and about 108 months at pH 5.0, without the need to add any other stabilizers such as EDTA in water in the presence of about 5% w / w from SAE-CD. This shelf life is longer than that described by Otterbeck (US Patent 5,914,122; up to six weeks at pH 4.0-6.0 in water in the presence of EDTA, ΗΡ-β-CD and other additives) .

The inventors also found that SAE-CD is capable of stabilizing budesonide isomers to different proportions. A study was conducted to determine whether SBE7-β-CD stabilized budesonide solutions and whether it preferably stabilized an isomer according to Example 13. Figure 11 is a semi-log plot of% initial concentration in each time point for samples stored at 60 ° C. Budesonide loss was first order at each temperature. The table below shows the pseudo first order rate constants calculated for each isomer at 60 ° C and 80 ° C.

<table> table see original document page 116 </column> </row> <table> <table> table see original document page 117 </column> </row> <table>

CAPTISOL

SBE7-P-CD stabilized both R and S isomers of budesonide in solutions at pH 4 and 6. The ratio of the rate constants with / without CAPTISOL was much less than 1 at all temperatures. SBE7-P-CD had a greater effect on the stability of both R and S isomers at pH 6 than at pH 4. At a given temperature, the ratio of rate constants with / without SBE7-P-CD was lower. Although SBE7-P-CD stabilized both isomers, S isomer appears to be stabilized to a greater extent than R. At all temperatures and pHs tested, the ratio of rate constants with / without SBE7-p-CD was lower for S isomer. The degree of stabilization affected by SBE7-p-CD at 60-C is greater than at 809C. An even greater degree of stabilization would be expected at 40 ° C and / or room temperature (20-30 ° C).

Samples of the above solutions were also placed in a chamber under a row of fluorescent lights. The small vials were periodically removed and tested for budesonide. Figure 12 shows the semi-log plot of the% of initial value remaining as a function of light exposure (light intensity * time). As noted in the table below, SBE7-p-CD significantly reduced budesonide photo decomposition. Budesonide loss was first order and independent of pH.

<table> table see original document page 118 </column> </row> <table>

The formulation of the invention may be provided as a kit adapted to form an inhalable nebulization solution. The kit may comprise a corticosteroid, SAE-CD, an aqueous vehicle, and optionally one or more other components. The corticosteroid and SAE-CD may be provided together or separately in solid, suspended or dissolved form. After mixing the SAE-CD with the corticosteroid in the presence of an aqueous vehicle, the solids will dissolve to form an inhalable solution rather than a suspension for nebulization. Each component may be provided in an individual container or together with another component. For example, SAE-CD may be provided in an aqueous solution, while budesonide is provided in dry solid or wet suspended form. Alternatively, SAE-CD is provided in dry form and budesonide is provided as an aqueous suspension, for example, PULMICORT RESPULES®. The kit may instead comprise a mixture of a solid derived cyclodextrin and solid corticosteroid and optionally at least one solid pharmaceutical carrier such that a major portion of the active agent does not complex with the previously derived cyclodextrin reconstituting the mixture with an aqueous vehicle. Alternatively, the composition may comprise a solid mixture comprising the inclusion complex of a derived cyclodextrin and an active agent, wherein a major portion of the active agent complexes with the derived cyclodextrin prior to reconstitution of the solid mixture with an aqueous carrier. Depending on the storage temperature of the kit, the aqueous vehicle may be a frozen liquid or solid. In one embodiment, the kit excludes the aqueous vehicle during storage, but the aqueous vehicle is added to the SAE-CD and corticosteroid prior to use to form the nebulization solution. The corticosteroid and SAE-CD may be complex and present in the aqueous concentrated form prior to the addition of the aqueous vehicle, which is then added to bring the solution to an appropriate volume and viscosity and concentration for nebulization. The formulation capable of being reconstituted may be prepared according to any of the following processes. Liquid formulation of the invention is first prepared, so a solid is formed by lyophilization (freeze drying), spray drying, spray freeze drying, anti-solvent precipitation, various processes using or near supercritical fluids. supercriticals, or other methods known to those skilled in the art to prepare a solid for reconstitution. Example 29 details a method for preparing a lyophilized solid composition or formulation comprising corticosteroids and SAE-CD by lyophilizing a liquid composition or formulation of the invention. The lyophilized solid may be dissolved in an aqueous liquid carrier prior to administration by nebulization. The dried powder would provide a stable form for long term storage and would also be useful for rapidly preparing larger-scale inhalation compositions, or as an additive for other inhalation solution medication to prepare combination products.

While the liquid composition or formulation of the invention may be administered to the lung, it would also be suitable for nasal, oral, ophthalmic, optical or topical administration. The liquid composition or formulation may also be administered by inhalation using a device such as a pump spray, metered dose inhaler, or pressurized metered dose inhaler. Accordingly, the invention provides a method of treating a costicosteroid responsive disease or disorder by administering the fluid to a patient in need of such treatment.

A liquid carrier (carrier) included in a formulation of the invention comprises an aqueous liquid carrier, such as water, aqueous alcohol, or aqueous organic solvent. Example 30 details the preparation of a liquid formulation comprising 20% weight / volume SAE-CD, corticosteroid, water and ethanol (0-5%). Increasing the concentration of ethanol in the liquid resulted in a decrease in maximal saturated corticosteroid solubility.

Although not necessary, the formulation of the present invention may include a conventional preservative, an antioxidant, a buffering agent, an acidifying agent, an alkalizing agent, a dye, a solubility enhancing agent, a complexes, an electrolyte, glucose, a stabilizer, a tonicity modifier, bulking agent, a defoaming agent, oil, an emulsifying agent, a cryoprotectant, a plasticizing agent, essences, sweeteners, a tonicity modifier, a surface tension modifier, a viscosity modifier, a density modifier, a volatility modifier, other excipients known to those skilled in the art for use in conserved formulations, or a combination thereof.

As used herein, the term "alkalizing agent" is intended to mean a compound used to provide alkaline medium, such as for product stability. Such compounds include, for example and without limitation, ammonia solution, ammonium carbonate, dieethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium, sodium hydroxide, triethanolamine, diethanolamine, organic amine base, alkaline amino acids and trolamine and others known to those skilled in the art.

As used herein, the term "acidifying agent" is intended to mean a compound used to provide an acidic medium for the stability of the product. Such compounds include, by way of example and without limitation, acetic acid, acetic amino acids, citric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid tartaric acid and nitric acid and others known to those skilled in the art.

The inclusion of a conventional preservative in the inhalable solution formulation is optional as the formulation is self-conserved by SAE-CD1 depending on its solution concentration. However, a conventional preservative may be additionally included in the formulation if desired. Preservatives may be used to inhibit microbial growth in the compositions. The amount of preservative is generally that necessary to prevent microbial growth in the composition for a storage period of at least six months. As used herein, a conventional preservative is a compound used to at least reduce the rate at which the bioburden increases, but preferably maintains the bioburden stationary or reduces the bioburden after contamination has occurred. Such compounds include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate , phenylmercuric acetate, thimerosal, metacresol, picolinium myristylgam chloride, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thymol, and methyl, ethyl, propyl or butyl parabens and others known to those skilled in the art.

As used herein, the term "antioxidant" is intended to mean an agent that inhibits oxidation and thus is used to prevent deterioration of preparations by the oxidative process. Such compounds include, by way of example and without limitation, acetone, potassium metabisulphite, potassium sulphite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, phosphorous, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulphite, sodium formaldehyde sulfoxylate, thioglycolic acid, EDTA, pentetate, and sodium metabisulfite, and others known to those skilled in the art. As used herein, the term "buffering agent" is intended to mean a compound used to prevent pH change with the dilution or addition of acid or alkali. Buffers are used in the present compositions to adjust the pH to a range of from about 2 to about 8, about 3 to about 7, or about 4 to about 5. example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, HEPES, lactic acid, tartaric acid, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, tris, sodium tartrate and anhydrous sodium citrate and dihydrate and others known to those skilled in the art. Other buffers include the citric acid / phosphate mixture, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvaine, phosphate, Prideaux- Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2- (N-morpholino) ethanesulfonic acid, BIS-TRIS (bis (2-hydroxyethyl) imino- tris (hydroxymethyl) methane), ADA (N- (2-acetamido) -2-imidiacetic acid), ACES (N- (carbamoylmethyl) -2-aminoethanesulfonic acid), PIPES (N, N piperazine acid '-bis (2-ethanesulfonic)), MOPSO (3- (N-morpholino) -2-hydroxypropanesulfonic acid), BIS-TRIS PROPANO (1,3-bis (tris (hydroxymethyl) methylamino) propane), BES (N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid), MOPS (3- (N-morpholino) propanesulfonic acid), TES (N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid), HEPES (N- (2-hydroxyethyl) piperazine-N '- (2-ethanesulfonic acid)), DIPSO (3- (N, N-bis (2-hydrochloric acid) oxyethyl) amino) -2-hydroxypropanesulfonic acid), MOBS (4- (N-morpholino) butanesulfonic acid), TAPSO (3- (N-tris (hydroxymethyl) methylamino) -2-hydroxypropanesulfonic acid), TRIZMA ® (tris (hydroxymethylaminomethane), HEPPSO (N- (2-hydroxyethyl) piperazine-N '- (2-hydroxypropanesulfonic acid), POPSO (piperazine-N, N, -bis (2-hydroxypropanesulfonic acid) ), TEA (triethanolamine), EPPS (N- (2-hydroxyethyl) piperazine-N '- (3-propanesulfonic acid)), TRICINE (N-tris (hydroxymethyl) methylglycine), GLY-GLY (glycylglycine) , BICINE (N, N-bis (2-hydroxyethyl) glycine), HEPBS (N- (2-hydroxyethyl) piperazine-N '- (4-butanesulfonic acid)), TAPS (N-tris (hydroxyethyl) methyl) methyl-3-aminopropanesulfonic acid), AMPD (2-amino-2-methyl-1,3-propadiodiol), and / or any other buffers known to those skilled in the art.

A complexing enhancing agent may be added to a formulation of the invention. When such an agent is present, the ratio of cyclodextrin / active agent may be changed. A complex formation enhancing agent is a compound or compounds which enhance the complex formation of the active agent with cyclodextrin. Suitable complexing enhancers include one or more pharmacologically inert water soluble polymers, hydroxy acids, and other organic compounds typically used in liquid formulations to enhance complex formation of a particular agent with cyclodextrins.

Hydrophilic polymers can be used as complexing enhancers, solubility enhancers and / or water activity reducers to improve the performance of formulations containing a cyclodextrin. Loftsson has described a number of polymers suitable for use in combination with a cyclodextrin (non-derivative or derivative) to enhance cyclodextrin performance and / or properties. Suitable polymers are described in Pharmazie (2001), 56 (9), 746-747; International Journal of Pharmaceutics (2001), 212 (1), 29-40; Cyclodextrin: From Basic Research to Market, International Cyclodextrin Symposium, 10th, Ann Arbor, M1, United States, May 21-24, 2000 (2000), 10-15 (Wacker Biochem Corp .: Adrian, Mich.); PCT International Publication No. WO 9942111; Pharmazie, 53 (11), 733-740 (1998); Pharm. Technol. Eur., 9 (5), 26-34 (1997); J. Pharm. Know. 85 (10), 1017-1025 (1996); European Patent Application EP0579435; Proceedings of the International Symposium on Cyclodextrins, 9th, Santiago de Comostela, Spain, May 31-June 3, 1998 (1999), 261-264 (Editor (s): La-Bandeira, JJ Torres; Vila-Jato, JL Kluwer Academic Publishers, Dordreich, The Netherlands); S.T.P. Pharma Sciences (1999), 9 (3), 237-242; ACS Symposium Series (1999), 737 (Polysaccharide Applications), 24-45; Pharmaceutical Research (1998), 15 (11), 1696-1701; Drug Development and Industrial Pharmacy (1998), 24 (4), 365-370; International Journal of Pharmaceuticals (1998), 163 (1-2), 115-121; Book of Abstracts, 216th ACS National Meeting, Boston, 23-27 August (1998), CELL-016, American Chemical Society; Journal of Controlled Release, (1997), 44/1 (95-99); Pharm.Res. (1997) 14 (11), S203; Investigative Ophthalmology & Visual Science, (1996), 37 (6), 1199-1203; Proceedings of the International Symposium on Controlled Release of Bioactive Materials (1996), 23rd, 453-454; Drug Development and Industrial Pharmacy (1996), 22 (5), 401-405; Proceedings of the International Symposium on Cyclodextrins, 8th, Budapest, March 31-April 2, (1996), 373-376. (Editor (s): Szejtli, J .; Szente1 L. Kluwer: Dordrecht, The Netherlands.); Pharmaceutical Sciences (1996), 2 (6), 277-279; European Journal of Pharmaceutical Sciences, (1996) 4 (SUPL.), S144; Third European Congress of Pharmaceutical Sciences Edinburgh, Scotland, UK 15-17 September 1996; Pharmazie (1996), 51 (1), 39-42; Eur. J. Pharm. Know. (1996), 4 (Suppl), S143; United States Patents Nos. 5,472,954 and No. 5,324,718; International Journal of Pharmaceutics (Netherlands), (Dec. 29, 1995) 126, 73-78; Abstracts of Papers of the American Chemical Society, (April 2, 1995) 209 (1), 33-CELL; European Journal of Pharmaceutical Sciences, (1994) 2, 297-301; Pharmaceutical Research (New York), (1994) 11 (10), S225; International Journal of Pharmaceutics (Netherlands), (April 11, 1994) 104, 181-184; and International Journal of Pharmaceutics (1994), 110 (2), 169-77, the entire disclosures of which are hereby incorporated by reference.

Other suitable polymers are well known excipients commonly used in the field of pharmaceutical formulations and are included, for example, in Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro (editor), Mack Publishing Company, Easton, PA, 1990 , pages 291-294; Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, Edition (Lea & Febinger, Philadelphia, PA, 1983, pp. 592-638); A.T. Florence and D. Altwood, (Physicochemical Principles of Pharmacy, Edition, MacMillan Press, London, 1988, pp. 281-334). The entire descriptions of the references cited herein are hereby incorporated by reference.

Still other suitable polymers include water-soluble natural polymers, water-soluble semisynthetic polymers (such as water-soluble cellulose derivatives) and water-soluble synthetic polymers. Natural polymers include polysaccharides such as inulin, pectin, algin derivatives (e.g. sodium alginate) and agar, and polypeptides such as casein and gelatin. Semisynthetic polymers include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, their mixed ethers such as hydroxypropyl methylcellulose and other mixed ethers such as hydroxyethyl ethylcellulose and hydroxypropyl ethylcellulose hydroxypropyl methylcellulose phthalate and carboxymethylcellulose and their salts, especially sodium carboxymethylcellulose. Synthetic polymers include polyoxyethylene (polyethylene glycols) derivatives and polyvinyl (polyvinyl alcohol), polyvinyl pyrrolidone and poly (styrene sulfonate) derivatives and various acrylic acid copolymers (eg carbomer). Other natural, semi-synthetic and synthetic polymers not specified herein which meet the criteria of water solubility, pharmaceutical acceptability and pharmacological inactivity are also considered to be within the scope of the present invention.

An emulsifying agent is intended to mean a compound that aids in the formation of an emulsion. An emulsifier may be used to moisten the corticosteroid and make it more receptive to dissolution. Emulsifiers for use herein include, but are not limited to, polyoxyethylene sorbitan fatty esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (Polysorbate 80), polysorbate 20 (polyoxyethylene monolaurate (20)). sorbitan), polysorbate 65 (polyoxyethylene tryptate (20) sorbitan), polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; lecithins; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propane-1,2-diol alginate; agar; carrageenan; locust bean gum; guar gum; tragacanth; acacia; xanthan gum; caraia gum; pectin; amidated pectin; ammonium phosphatides; microcrystalline cellulose; methylcellulose; hydroxypropylcellulose; hydroxypropyl methylcellulose; ethyl methylcellulose; carboxymethylcellulose; sodium, potassium and calcium salts of fatty acids; fatty acid mono- and diglycerides; acetic acid esters of fatty acid mono- and diglycerides; fatty acid mono- and diglyceride lactic acid esters; citric acid esters of fatty acid mono- and diglycerides; tartaric acid esters of fatty acid mono- and diglycerides; mono- and diathyltartaric acid esters of fatty acid mono- and diglycerides; mixed acetic and tartaric acid esters of fatty acid mono- and diglycerides; sucrose fatty acid esters; saccharoglycerides; polyglycerol esters of fatty acids; polyglycerol esters of castor oil polycondensated fatty acids; propane-1,2-diol fatty acid esters; sodium stearoyl-2-lactylate; calcium stearoyl-2-lactylate; stearoyl tartrate; sorbitan monostearate; sorbitan trystearate; sorbite monolaurate; sorbitan monooleate; sorbitan monopalmitate; quaia extract; dimerized fatty acid polyglycerol esters of soybean oil; oxidatively polymerized soybean oil; and pectin extract.

As used herein, the term "stabilizer" is intended to mean a compound used to stabilize the therapeutic agent against the physical, chemical, or biochemical process that would reduce the therapeutic activity of the agent. Suitable stabilizers include, by way of example and without limitation, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryphonate, zinc oxide, sucrose, glucose, lactose. sorbitol, mannitol, glycerol, polyethylene glycols, sodium caprylate and sodium saccharin and others known to those skilled in the art.

As used herein, the term "tonicity modifier" is intended to mean a compound or compounds that may be used to adjust the tonicity of the liquid formulation. Suitable tonicity modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose and others known to those skilled in the art. Other tonicity modifiers include both inorganic and organic tonicity adjusting agents. Tonicity modifiers include, but are not limited to, ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, sodium bismuth tartrate, boric acid, chloride Calcium, Disodium Calcium Edetate, Calcium Glyconate, Calcium Iactate, Citric Acid, Dextrose, Diethanolamine, Dimethyl Sulphoxide, Disodium Edetate, Trisodium Edetate Monohydrate, Sodium Fluorescein, Fructose, Galactose, Glycerin, Lactic Acid, Lactose Chloride magnesium, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chloride, potassium chloride, potassium iodide, potassium nitrate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium bisphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride io, sodium citrate, sodium iodide, sodium iodate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfate, sodium tartrate , sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethane, uridine and zinc sulfate. In one embodiment, the tonicity of the liquid formulation resembles the tonicity of the tissues in the respiratory tract.

An osmotic agent may be used in the compositions to increase overall patient comfort with the distribution of the corticosteroid composition. Osmotic agents may be added to adjust the tonicity of SAE-CD containing solutions. Osmolality is related to the concentration of SAE-CD in water. At SBE7-p-CD concentrations below about 11-13% w / v, the solutions are hypotonic or hypoosmotic to blood, and at SBE7-P-CD concentrations above about 11-13% w / v. / v, SBE7-P-CD containing solutions are hypertonic or hyperosmotic with respect to blood. When red blood cells are exposed to solutions that are hypo- or hypertonic, they may shrink or swell in size, which may result in hemolysis. As noted above and in Figure 1, SBE-CD is less likely to induce hemolysis than other derived cyclodextrins. Suitable osmotic agents include any low molecular weight water soluble species pharmaceutically approved for pulmonary and nasal delivery such as sodium chloride, lactose and glucose. The formulation of the invention may also include biological salt (s), sodium chloride, or other electrolyte (s).

As used herein, the term "defoaming agent" is intended to mean a compound or compounds that prevent or reduce the amount of foam that forms on the surface of the liquid formulation. Suitable defoaming agents include dimethicone, symmetic, octoxynol, ethanol and others known to those skilled in the art.

As used herein, the term "bulking agent" is intended to mean a compound used to add bulk to the lyophilized product and / or to assist in controlling the properties of the formulation during lyophilization. Such compounds include, by way of example and without limitation, dextran, trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol, dimethyl sulfoxide, glycerol, albumin, calcium lactobionate , and others known to those skilled in the art.

As used herein, the term "cryoprotectant" is intended to mean a compound used to protect an active therapeutic agent from physical or chemical degradation during lyophilization. Such compounds include, by way of example and without limitation, dimethyl sulfoxide, glycerol, trehalose, propylene glycol, polyethylene glycol, and others known to those skilled in the art.

A solubility enhancing agent may be added to the formulation of the invention. A solubility enhancing agent is a compound, or compounds, which enhances the solubility of the active agent when in an aqueous liquid carrier. When another solubility enhancing agent is present, the ratio of cyclodextrin / active agent may be changed. Suitable solubility enhancing agents include one or more cyclodextrins, cyclodextrin derivatives, SAE-CD1 organic solvents, detergents, soaps, surfactant and other organic compounds typically used in parenteral formulations to enhance the solubility of a particular agent. Exemplary solubility enhancers are described in United States Patent No. 6,451,339; however, other surfactants used in the pharmaceutical industry may be used in the formulation of the invention. Suitable cyclodextrins include non-derivative cyclodextrins and cyclodextrin derivatives such as SAE-CD, SAE-CD derivatives, hydroxyalkyl ether cyclodextrin and derivatives, alkyl ether cyclodextrin and derivatives, sulfated cyclodextrin and derivatives. , hydroxypropyl-β-cyclodextrin, 2-β-β-CD, methyl-β-cyclodextrin, carboxyalkyl thioether derivatives, sucinyl cyclodextrin and derivatives, and other cyclodextrins suitable for pharmaceutical use. SAE-CD cyclodextrins are particularly advantageous.

Suitable organic solvents that may be used in the formulation include, for example, ethanol, glycerine, polyethylene glycols, propylene glycol, poloxomers, and others known to those skilled in the art.

It should be understood that compounds used in the art of pharmaceutical formulations generally perform a variety of functions or purposes. Thus, if a compound specified herein is mentioned only once or is used to define more than one term included herein, its purpose or function should not be construed as being limited solely to that purpose (s) ( specified function (s).

An active agent contained within the present formulation may be present as its pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" refers to derivatives of the described compounds wherein the active agent is modified by reacting it with an acid or base as necessary to form an ionically bound pair. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Suitable non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known to those skilled in the art. Salts prepared from organic acids, such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanyl, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, disulfonic, oxalic, isethionic ethane, and others known to those skilled in the art. The pharmaceutically acceptable salts of the present invention may be synthesized from the parent active agent which contains a basic or acidic moiety by conventional chemical methods. Lists of other suitable salts are found in Remington's Pharmaceutical Sciences, 17a. ed., Mack Publishing Company, Easton, PA, 1985, the relevant disclosure of which is hereby incorporated by reference.

The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human tissues. and animals, without excessive toxicity, irritation, allergic response, or other commensurate problem or complication with a reasonable benefit / risk ratio.

As used herein, the term "patient" is used to mean warm-blooded animals such as mammals, for example, deer, dogs, mice, guinea pigs, horses, deer - cas, sheep and humans.

A formulation of the invention will comprise an active agent present in an effective amount. By the term "effective amount" is meant the amount or amount of active agent sufficient to elicit the required or desired response, or in other words, the amount sufficient to elicit an appreciable biological response. when administered to a patient.

In view of the above description and examples below, one skilled in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples, which detail certain procedures for preparing formulations in accordance with the present invention. All references made to these examples are for illustration purposes. The following examples should not be considered exhaustive, but merely illustrative of only some of the many embodiments contemplated by the present invention.

EXAMPLE 1

Illustrative formulations according to the invention were prepared according to the following general procedures.

Method A

Cyclodextrin is dissolved in water (or buffer) to form a solution containing a known concentration of cyclodextrin. This solution is mixed with an active agent in the form of solid, suspension, gel, liquid, paste, powder or other form while mixing, optionally while heating, to form an inhalable solution.

Method B

A known amount of substantially dry cyclodextrin is mixed with a known amount of substantially dry active agent. A liquid is added to the mixture to form a suspension, gel, solution, syrup or paste, while mixing, optionally while heating, and optionally in the presence of one or more other excipients, to form an inhalable solution. .

Method C

A known amount of substantially dry cyclodextrin is added to a suspension, gel, solution, syrup or paste comprising a known amount of active agent while mixing, optionally while heating, and optionally in the presence of one or more plus other excipients to form an inhalable solution.

The methods of this example may be modified by the inclusion of a wetting agent in the composition to facilitate dissolution and complex formation by subsequent inclusion of the corticosteroid. A surfactant, soap, detergent or emulsifying agent may be used as a wetting agent.

Method D

To a solution comprising a known concentration or amount of SAE-CD, aqueous liquid carrier, and optionally one or more other excipients, a molar excess of the carticosteroid based on the molar ratio of SASE-CD to corticosteroid at the solubility point is added. saturated corticosteroid, in the presence of SAE-CD, as determined here. For example, corticosteroids would be added in a molar excess of 5%, 10%, 15%, 20%, 25%, 30% or greater. The components are mixed to equilibrium, at which point there is only a minor change in budesonide concentration over a one hour time period. Then excess corticosteroid is removed leaving behind the target solution of the invention.

Budesonide is added to the solution containing SASE-CD as a solid or suspension in an aqueous liquid carrier, which may be water, buffer, aqueous alcohol, aqueous organic solvent or a combination thereof. Alcohol and organic solvent of a pharmaceutically acceptable grade, such as ethanol, propylene glycol, and others as described herein.

Method E

SAE-CD and corticosteroids are ground to form a mixture. Then an aqueous liquid carrier is added to the mixture of the target solution of the invention.

Grinding may be conducted dry or in the presence of moisture, water, buffer, alcohol, surfactant, organic solvent, glycerin, poly (ethylene glycol), poloxamer, or a combination thereof.

Method F

Any of the included methods are conducted in the presence of heat, for example at a temperature of at least 40 ° C.

G method

Any of the included methods are conducted with cooling, for example, at a temperature of less than 20 ° C or less than 100 ° C or less than 5 ° C.

Method H

Any of the included methods are conducted in the presence of high shear mixing such as with a sonicator, narrow gauge syringe (s), mixer / homogenizer (POLYTRON from KINEMATICA, Europe; FLUKO, Shanghai, China; ULTIMAGRAL from GEA Niro, Inc., Columbia, MD), rotor-stator mixer, or sawtooth mixer. Method I

Any of the included methods is conducted under reduced pressure.

EXAMPLE 2

The MMD of nebulized solutions containing SBE7-P-CD and budesonide was determined as follows.

Placebo solutions of three different cyclodextrins were prepared at different concentrations. Two ml of the solutions were added to the vessel of a Pari LC Plus nebulizer supplied with air from a Pari Proneb Ultra compressor. The particle size of the emitted droplets was determined using a Malvern Mastersizer S laser light scanning instrument.

EXAMPLE 3

The stability of SAE-CD-containing liquid formulations was determined by HPLC chromatography of periodically removed aliquots from the storage liquid.

Citrate phosphate buffer solutions (Mcllvaines), at a pH of 4, 5, 6, 7, or 8, were prepared by mixing several portions of 0.01 M citric acid with 0.02 M Na2 HPO4. These stock solutions contained 5% w / w Captisol. Approximately 250 μg / mL budesonide was dissolved in each buffer solution. Aliquots of the solutions were stored at 40 ° C, 50 ° C and 60 ° C. Control samples were stored at 5 ° C, but are not described here. HPLC analysis of the samples was performed initially and after 1, 2, and 3 months of storage.

HPLC conditions included:

<table> table see original document page 134 </column> </row> <table>

EXAMPLE 4

The viscosity of aqueous solutions containing SAE-CD was measured using a cone and plate viscometer.

A Brookfield DV-III + Programmable Rheometer, CPE-40 cone and CPE 40Y plate (Brookfield Engineering Laboratories, Middleboro, MA) was used to make measurements on 0.5 ml samples at 1, 2, 3, 5 and 10 rpm. . Samples were sheared for approximately 5 revolutions prior to each measurement. This allowed the accurate rheological characterization of the samples. The temperature of all samples was equilibrated to 25 +/- 1 degrees centigrade using a double-walled viscometer cone supplied with water from an electronically controlled thermostatic circulating water bath (Model, 8001, Fisher Scientific, Pittsburgh, PAN). The viscometer was calibrated using 5 and 50 centipoise using silicon oil calibration standards. Viscosity measurements were made at 5 or more rotational speeds to achieve shear thinning behavior (viscosities that decrease as shear rate increases). Higher rotational speeds resulted in increased shear rates.

EXAMPLE 5

The nebulizer output rate as a function of SAE-CD concentration was measured according to the following general procedure.

Nebulizer Output was tested using Pari LC Plus Nebulizer with a Pari ProNeb Ultra Air Compressor (Minimum Nebulizer Volume = 2 ml, Maximum Nebulizer Volume = 8 ml) for solutions containing 43%, 21.5%. , 10.75% and 5.15% w / w SBE7-β-CD. The percentage of emitted sample was estimated in a gravimetric manner. The nebulizer vessel was weighed before and after nebulization was complete. Nebulization Time was defined as the time duration when the nebulizer run was started until the time of the first crackle. The Nebulizer Exit Rate was calculated by dividing the% Issued with Nebulization Time.

EXAMPLE 6

Preparation of an inhalable solution containing budesonide.

A buffer solution containing 3 mM Citrate Buffer and 82 mM NaCl at pH 4.45 is prepared. -12.5 grams of CAPTISOL were placed in a 250 ml volumetric flask. -62.5 mg budesonide were placed in the same vial. The vial was completed to volume with 3 mM citrate buffer solution / 82 mM NaCl. The vial was mixed well over a 10 minute spinner and sonicated for 10 minutes. The flask was shaken over the weekend with magnetic stirrer. Stirring was stopped after -62 hours and the vial was again swirled and sonicated again for 10 minutes each. The solution was filtered through a 0.22 μιτι Durapore Millex-GV Millipore syringe filter unit. The first few drops were discarded before resting the filter solution in an amber glass jar with a Teflon coated screw cap. The sample concentration was -237 μg / ml.

EXAMPLE 7

Preparation of an inhalable solution containing budesonide.

Approximately 5 grams of CAPTISOL was placed in a 100 mL volumetric flask. -26.3 mg budesonide was placed in the same vial. The vial was completed to volume with 3 mM citrate buffer solution / 82 mM NaCl. The mixture was mixed well over a 10 minute spinning apparatus and sonicated for 10 minutes. The mixture was stirred overnight with a magnetic stirrer. Stirring was stopped after -16 hours and the vial was again swirled and sonicated again for 10 minutes each. The solution was filtered through a 0.22 μη Durapore MiIIex-GV Millipore syringe filter unit. The first 5 drops were discarded before resting the filter solution in an amber glass jar with a Teflon coated screw cap. The sample was analyzed to be 233 μg budesonide / ml.

EXAMPLE 8

Preparation of an inhalable solution containing budesonide. The procedure of Example 7 was followed except that 12.5 g CAPTISOL, 62.5 mg budesonide and about 250 ml buffer were used. Sufficient disodium EDTA was added to prepare a solution having an EDTA concentration of about 0.01 or 0.05% w / v EDTA.

EXAMPLE 9

Preparation of a solution containing SAE-CD and budesonide as prepared from a suspension of PULMICORT RESPULES.

Method A

About 50 mg (corrected for water content) of CAPTISOL was added per mL of Respule to the contents of one or more Pulmicort Respules containers (nominally 2 mL of the suspension) and mixed or shaken well by several. minutes After resting for about 30 minutes to several hours, the solution was used as is for in vitro characterization. In addition to budesonide and water, PULMICORT RESPULE (suspension) also contains the following active ingredients for each label: citric acid, sodium citrate, sodium chloride, disodium EDTA and polysorbate 80.

Method B

Weigh approximately 200 mg of water-corrected CAPTISOL into 3.544 gram amber flasks (2 drachmas). Pour the contents of the two Pulmicort Respirates containers (0.5 mg / 2 mL Lot # 308016 Feb05) into each small bottle containing the heavy amount of CAPTISOL by gently compressing the deformable plastic container to the last possible drop. The Respules were previously swirled to resuspend the budesonide particles. The vials were capped with screw caps, vigorously swirled and then wrapped in foil. Material can be kept refrigerated until use.

The inhalable liquid composition prepared according to any of these methods may be used in any known nebulizer. By converting the suspension into a liquid, an improvement in the distribution of budesonide (a corticosteroid) is observed.

Example 10

Other solutions according to the invention may be prepared as detailed below.

<table> table see original document page 137 </column> </row> <table>

• Dilute Concentrate A 1 to 4 with pH 4.5 saline citrate buffer (4 mM containing 109 mM sodium chloride) containing 5% w / v CAPTISOL on an anhydrous basis. Filter the diluted concentrate through a 0.22 μm Millipore Durapore Millex-GV syringe filter unit. Test the filtered solution by HPLC, then add supplemental budesonide as needed to give a final solution concentration of about 250 µl / ml (± <5%).

• Dilute Concentrate B1 1 to 4 with pH 4.5 saline citrate buffer (4 mM containing 109 mM sodium chloride) containing 5% w / v CAPTISOL on an anhydrous basis. Filter the diluted concentrate through a 0.22 μιη Millipore Durapore Millex-GV syringe filter unit. Test the filtered solution by HPLC, then further dilute with pH 4.5 saline citrate buffer (3 mM containing 82 mM sodium chloride) containing 5% w / v CAPTISOL as required to give a final concentration of about 250 pg / mL (± <5%). This technique takes advantage of the excess solid budesonide used to saturate the solution.

EXAMPLE 11

The clarity of the solutions was determined by visual or instrumental inspection. A clear solution is at least clear by visual inspection with the eye without assistance.

EXAMPLE 12

The following method was used to determine the performance of nebulization compositions emitted from a nebulizer according to FIGS. 10a-10b.

Two ml of the CD solution or Pulmicort test suspension was accurately pipetted by volumetric pipettes into a clean nebulizer well before starting each experiment. The test nebulizer was mounted and loaded with the test inhalation solution or suspension according to the manufacturer's instructions. The end of the nozzle was placed at a height of approximately 18 cm from the MALVERN MASTERSIZER platform to the midpoint of the nebulizer nozzle tip. A vacuum source was positioned opposite the nozzle approximately 6 cm apart to expel the aerosol after classification. The distance between the nozzle and the detector was approximately 8 cm. The center of the nozzle was leveled with the laser beam (or adjusted as appropriate depending on the individual design of each nebulizer). The laser has crossed the center of the mist emitted when the nebulizer is running. Measurements were started manually 15 seconds in nebulization. Data collection began when beam obscuration reached 10% and averaged over 15,000 scans (30 seconds). The light intensity data scattered over the detector rings was modeled using the "Stanard-Wet" model. Channels 1 and 2 were extinguished due to low relative humidity during measurement to prevent beam conduction. The droplet volume diameter was determined by defining 10, 50 (volume mean) and 90% of the smallest cumulative volume. (Dv10 is the size below which there is 10% of the material volume, Dv50 is the size below which there is 50% of the material volume and Dv90 is the size below which there is 90% of the material volume).

EXAMPLE 13

Budesonide solutions, with and without SBE7-P-CD, were prepared at two different pHs (4 and 6) and stored at 2 different temperatures (60 ° C and 80 ° C). Citrate buffers (50 mM) at each pH value were prepared by mixing different portions of 50 mM citric acid and 50 mM sodium citrate solutions (tribasic, dihydrates). To achieve a budesonide concentration in buffers without SBE7-P-CD sufficient for accurate measurement, budesonide was first dissolved in 100% ethyl alcohol. An aliquot of the ethanol / budesonide solution was then added dropwise with stirring to each buffer solution. The theoretical budesonide concentration was 100 pg / mL with a final ethanolic content of 5% in each buffer. All solution preparations and budesonide procedures were done in a darkened space under red light. After stirring the solutions for 24 hours, both buffer solutions were filtered through 0.22 μm Millipore MiIIex-GV syringe filters to remove any precipitated solid (no significant amount observed) from the solutions. The final budesonide concentration was about 50 μg / mL. Both pH 4 and 6 solutions were divided into two, and solid SBE7-P-CD was added to one portion to create solutions with and without 1% w / v. SBE7-P-CD at each pH. Each solution was aliquoted into individual small amber vials. They were then placed in ovens at 60 ° C and 80 ° C. Small sample vials were removed from the ovens and analyzed by HPLC at 0, 96, 164, and 288 hours. HPLC assay conditions were summarized below.

Chromatographic Conditions

(Adapted from Hou, S., Hindle, M., and Byron, P. R. A. Stability-Indicating H-PLC Assav Method for Budesonida. Journal of Pharmaceutical and Biomedical Analysis, 2001; 24: 371-380.)

<table> table see original document page 140 </column> </row> <table>

EXAMPLE 14

Preparation and use of a combination solution containing SAE-CD, budesonide, and albuterol sulfate.

A budesonide solution is prepared according to EXAMPLE 9 (by mixing SAE-CD with the PULMICORT RESPULES suspension) and added to 3 ml of a solution containing 2.5 mg albuterol (The World Health Organization recommended name for albuterol is salbutamol), supplied as albuterol sulfate. Albuterol solution is commercially available prediluted and sold under the name PROVENTIL® Inhalation Solution, 0.083%, or is prepared from a commercially available 0.5% concentrate (sold under the names: PROVENTIL® Solution for inhalation and VENTOLIN® Inhalation Solution).

To provide the required dose for children 2 to 12 years of age, the initial dosage should be based on body weight (0.1 to 0.15 mg / kg per dose), with the subsequent dosage titrated to achieve the appropriate response. is the desired clinic. The dosage should not exceed 2.5 mg three to four times daily by nebulization. The appropriate volume of 0.5% inhalation solution should be diluted in sterile normal saline to a total volume of 3 mL prior to administration via nebulization. To provide 2.5 mg, 0.5 mL of the concentrate is diluted to 3 mL with sterile normal saline. The albuterol aqueous solutions also contain benzalkonium chloride; and sulfuric acid is used to adjust the pH to between 3 and 5. Alternatively, an aqueous solution of an appropriate albuterol concentration may be prepared from albuterol sulfate, USP, with or without added preservative benzalkonium chloride, and pH adjustment using sulfuric acid may also be unnecessary when combined with corticosteroid solution. In addition, the volume containing the appropriate dose of corticosteroid may be decreased fourfold, as described in the following example, allowing the total volume to be decreased and administration time to be decreased thereby.

EXAMPLE 15

Preparation and use of a combination solution containing SAE-CD, budesonide, and albuterol sulfate or Ievalbuterol HCI (Xopenex).

A citrate buffer (3 mM pH 4.5) was prepared as follows. Approximately 62.5 mg of citric acid was dissolved in, and brought to volume with water in a 100 ml volumetric flask. Approximately 87.7 mg of sodium citrate was dissolved in, and brought to volume with, water in another 100 mL volumetric flask. In a beaker, the sodium citrate solution was added to the citric acid solution until the pH was approximately 4.5.

Approximately 10.4 mg of budesonide and 1247.4 mg of captisol were ground together with a gral and a pestle and transferred to a 10 mL flask. Buffer solution was added, and the mixture was removed, sonicated and an additional 1.4 mg of budesonide added. After stirring overnight, the solution was filtered through a 0.22 μιη Durapore MiIIex-GV Millipore Syringe Filter Unit. The resulting budesonide concentration was ~ 1 mg / ml. Approximately 0.5 ml of the bude-sonide solution was added to a unit dose of Proventil (2.5 mg / 3 mL) or Xopenex (1.25 mg / 3 mL), thereby forming the liquid dosage form. clear in combination of the invention. The resulting mixture remained essentially clear for at least 17 days under ambient room conditions, protected from light.

Example 16

Preparation and use of a combination solution containing SAE-CD, budesonide, and formoterol (FORADIL® (formoterol fumarate inhalation powder)).

The contents of a capsule containing 12 mcg of formoterol fumarate combined with 25 mg of lactose were poured into a small vial to which 3 mL of 3 mM citrate buffer (pH 4.5) was prepared as described. in the previous example. The contents of the small vial were swirled to dissolve the solids present. Budesonide concentrate was prepared as described in the previous example to provide a concentration of -1 mg / mL. Approximately 1 ml of the budesonide solution was added to the formoterol fumarate buffered solution. The resulting solution remained essentially clear for at least one month under ambient conditions, protected from light.

Example 17

Clinical evaluation of a dosage form according to the invention was conducted by performing gamma scintigraphy analyzes on patients before and after administration of the dosage form by nebulization.

A four-way, single center crossover gamma scintigraphy study was conducted to compare the pulmonary distribution of budesonide via the Pulmicort Respules®, and Captisol-Enabled® budesonide formulations using a Pari LC air jet nebulizer . The purpose of the study was to determine by gamma scintigraphy the intrapulmonary deposition of radiolabelled budesonide after nebulization of a bude-sonide suspension (Pulmicort Respules®, Astra Zeneca, reference formulation) and a CaptisoP-EnabIed budesonide solution test) in healthy male volunteers. Dosing was conducted using a Pari LC Plus air jet nebulizer. The use of gamma scintigraphy in conjunction with the drug and / or radiolabelled study vehicle is the standard technique for the quantitative assessment of pulmonary deposition and clearance of inhaled drugs and / or vehicle.

The study dosage forms consisted of: 1) 1 mg Budesonide as 2mLx 0.5 mg / mL Pulmicort Respules®; or 2) 1 mg Budesonide as 2 mL χ 0.5 mg / mL Pulmicort Respules to which 7.5% w / v Captisol® had been added.

Each patient received each of the four study administrations of radiolabelled Budesonide in a non-randomized manner. A non-randomized design was used for this study as the reference formulation (Pulmicort Respule®) must be administered first to all patients to determine the time to crackle (TTS). TTS differed between patients. For subsequent administrations, the administered dose was controlled by the duration of administration, expressed as a fraction of the time until crackling, determined following administration of the reference formulation (ie 25% TTS, 50% TTS and 75%). % of TTS). It was expected that although the same concentration of budesonide would be nebulized for a shorter time, the amount of drug reaching the volunteers' lungs was essentially the same as the reference suspension for one of the study steps. Scintigraphic images were acquired using a gamma camera immediately after dosing of volunteers.

Comparison of the reference product image and the 25% TTS step indicated that a greater percentage of budesonide from Respule was in the stomach and throat immediately after administration. Thus, a greater percentage of budesonide reached the target lung tissue when Captisol was used to dissolve budesonide.

This could reduce the undesirable side effects caused by the drug. One aspect of the method and dosage form of the invention thus provides an improved method of administering a unit dose to the corticosteroid suspension base, the method comprising the step of adding a sufficient amount of SAE-CD to convert the suspension to a clear solution and then administer the clear solution to a patient. As a result, the method of the invention provides increased administration rate as well as increased total pulmonary corticosteroid distribution compared to the initial unit dose suspension formulation.

EXAMPLE 18

Comparative evaluation of various forms of SAE-CD in the solution of corticosteroid derivatives.

The solubility of beclomethasone dipropionate (BDP), beclomethasone 17-monopropionate (B17P), beclomethasone 21-monopropionate (B21P) and beclomethasone (non-esterified) in solutions containing CAPTISOL and several SBEnY-CDs were evaluated. BDP, B17P and B21P were obtained from Hovione. Beclomethasone was obtained from Spectrum Chemicals. CAPTISOL, SBE (3.4) γ-CD, SBE (5.23) γ-CD and SBE (6.1) γ-CD were provided by CyDex, Inc. (Lenexa, KS). Γ-CD was obtained from Wacker Chemical Co. SBE (5.24) γ-CD and SBE (7.5) γ-CD were provided by the University of Kansas.

A 0.04M solution was prepared from each selected CD. Each form of beclomethasone required 2 ml of CD solution, so 0.04 M solutions were prepared in duplicate 20 or 25 ml volumetric flasks (N = 2). The following table indicates the amount of each CD used after recording the water content on each CD. <table> table see original document page 145 </column> </row> <table>

Beclomethasone forms were weighed in excess of the predicted solubilities directly into small 3.544 gram (2 drach) Teflon-coated screw-capped vials. These amounts typically provided approximately 6 mg / mL solids. Each small vial then received 2 ml of the appropriate CD solution. The vials were swirled and sonicated for about 10 minutes to aid in wetting the solids with the fluid. The vials were then wrapped in aluminum foil to protect from light and placed on a laboratory vibrator for balance. The flasks were periodically inspected visually to ensure that the solids were properly moistened and in contact with the fluid. Time points to sample were 24 h for all shows and 72 hours for BDP only.

SBE (6.1) γ-CD solutions were prepared at 0.04, 0.08, and 0.1 M and SBE (5.23) γ-CD solutions were prepared at only 0.04 and 0.08M. Beclomethasone dipropionate was weighed in excess of the expected solubilities directly into small Teflon-coated screw-capped vials of 3,544 grams (2 drachmas). These amounts typically provided approximately 2 mg / mL solids. Each small vial then received 2 ml of the appropriate CD solution (N = 1). The vials were swirled and sonicated for about 10 minutes to aid in wetting the solids with the fluid. The vials were then wrapped in aluminum foil to protect from light and placed on a laboratory vibrator for equilibration for five days.

Γ-CD solutions were prepared at 0.01 and 0.02M. Beclomethasone dipropionate was weighed in excess of the expected solu- tities directly into small Teflon-lined screw-capped vials of 3,544 grams (2 drachmas). These amounts typically provided approximately 2 mg / mL solids.

Each small vial then received 2 ml of the γ-CD solution (N = 2). A solution was also prepared to measure the intrinsic solubility of BDP using HPLC grade water in place of CD. The samples were wrapped in foil and placed on a laboratory vibrator for five days.

At the end of the equilibration time for each stage, the vials were centrifuged and 1 ml of supernatant removed. The removed supernatant was then filtered using the 0.22 μm Durapore PVDF syringe filter (discarding the first few drops), and diluted with the mobile phase to an appropriate concentration within the standard curve. Samples were then analyzed by HPLC to determine the concentration of solubilized corticosteroids.

Example 19

Preparation and use of a combination solution containing SAE-CD1 budesonide, and formoterol fumarate.

Formoterol fumarate dry powder is mixed with Captisol dry powder, which are both appropriately sized to provide content uniformity at a weight ratio of 12 mcg formoterol fumarate / 100 mg Captisol. An amount of the powder combination corresponding to a unit dose of formoterol fumarate is either placed in a suitable unit dose container such as an HPMC capsule for later use or added directly to a single dose of suspension. Budsonide Pulmicort Respules (500 mcg / 2mL) inhalation tube, then mixed to dissolve all solids (a clear solution) and placed in the nebuliser reservoir for administration.

EXAMPLE 20

Preparation and use of a combination solution containing SAE-CD, budesonide, and ipratropium bromide. A budesonide solution according to EXAMPLE 9 is prepared and added to a commercially available ipratropium bromide solution and sold under the name ATROVENT® Inhalation Solution Single Dose. The ATROVENT® Inhalation Solution (ipratropium bromide) is 500 mcg (1 unit dose vial), administered three to four times daily by oral nebulization, at doses 6 to 8 hours apart. ATROVENT® inhalation solution unit dose vials contain 500 mcg of anhydrous ipratropium bromide in 2.5 ml sterile, preservative-free isotonic saline adjusted to pH 3.4 (3 to 4) with hydrochloric acid.

In addition, the volume containing the appropriate corticosteroid dose can be decreased fourfold, as described in the above example (budesonide concentration ~ 1 mg / mL), allowing the total volume to be decreased and administration time to be decreased accordingly.

EXAMPLE 21

Evaluation of the AERONEB GO nebulizer versus a RAINDROP nebulizer with a solution comprising budesonide, aqueous liquid carrier and SAE-CD.

The AERONEB GO Nebulizer (AEROGEN Inc., Mountainview, California) is detailed in Power and others United States Pregrant Publication No. 2005-011514 (Application USSN 10 / 833.932 filed April 27, 2004), PCT International Publication WO 2005 No. 009323 to Aerogen, Inc. and others (PCT Application No. PCT / US 2004/021268 filed July 6, 2004), and European Application No. EP 16426276, the entire descriptions of which are hereby incorporated by reference.

The RAINDROP nebulizer is available from Nellcor (Tyco Healthcare).

The solution of the invention used for this study was prepared according to Example 28.

The droplet size distribution characterization of an aerosolized solution using a cascade impactor was determined according to Example 26.

Determination of drug exit and drug exit rate from a liquid-containing nebulizer of the invention was determined according to Example 27.

EXAMPLE 22

Evaluation of United States Patent No. 6,962,151 pulsatile membrane nebulizer with a solution comprising bude-sonide, aqueous liquid carrier and SAE-CD. Inert Impact Characterization of Tc99m-DTPA Labeled Captisol-Enableó® Budesonide Aerosols Generated via Pari Electronic Nebulizer.

The nebulizer detailed in U.S. Patent No. 6,962,151 is also described in PCT International Application No. PCT / US 00/29541 filed October 27, 2000, and Serial Application No. 11 / 269,783 filed in November 7, 2005.

Aerosol characterization was conducted by standard in vitro inert impaction tests using an Andersen Cascade Impactor (ACI). Technetium - 99m (99mTc), in the form of diethylenetriaminapentaacetic acid (DTPA, GE Healthcare), was added to Captisol-Enabled® Borsonide Inhalation Solution (CEBUD). The suitability of 99mTc-DTPA to function as a substitute for budesonide in CEBUD preparations has been valid in the course of previous clinical experience (see Example 17). Preparation of the budesonide solution formulation for testing was conducted as per the description below. It has been estimated that approximately 99mTc IOMBq should be added to the budesonide formulation (11.05 g) on the day of the test to provide sufficient activity for in vitro imaging.

Two Pari electronic vibrating membrane nebulizers were used. At the core of this electronic nebulizer is a stainless steel membrane with thousands of laser-drilled holes. Laser drilling allows flexibility to customize particle size, ensure reproducibility, and maintain a high output rate with smaller particles. The perforated membrane is vibrated at high frequencies in a resonant "bend" mode that produces high particle output rates. The nebulizer provides rapid drug distribution, efficiency, ideal particle size measurement, low residual volume, and optimal performance compared to inhaled drug formulation (See Rajiv Dhand, Respiratory Care 2002; (12): 1406 - 1416). Approximately 0.5 mL of drug solution was loaded and subsequently distributed through each nebulizer on 3 separate occasions. Cycles 1, 3 and 5 were conducted with Device 1 and cycles 2, 4 and 6 were conducted with Device 2. Pre-dose

On each occasion, prior to dose distribution, the charged nebulizer was imaged for 60 seconds in Head I of the dual head gamma camera (Axis, Philips Medical Systems). In addition, nebulizers were weighed before and after the addition of the budesonide formulation.

Inert Impact Test

The nebulizer was positioned at the USP (United States Pharmacopoeia) inlet of the ACI and a flow rate of 28.3 L / min. was extracted from the impactor using a vacuum pump. The flow through the impactor was started before the activation of the electronic nebulizer. A stopwatch was used to measure the duration of dose distribution.

The ACI test conditions were the same as those used for evaluation of the Pari LC Plus air jet nebulizer in the course of the previous clinical study.

Following deposition, USP throat was removed from the ICA and imaged for 120 seconds. The collection plates were removed from the printer and placed on the Gamma camera Head I and imaged for 120 seconds. The plates were subsequently washed and dried prior to conducting other impaction tests. Post dose

At each occasion, the nebulizing weight was recorded after dose distribution. The nebulizer was imaged as described below. Image Processing

A rectangular ROI was applied to image for the nebulizer pre-dose. This ROI was then reapplied to image the nebulizer after dose distribution. A rectangular ROI was also applied to the "USP Inlet Image".

A circular ROI was taken around collection plate O, copied and placed around plate 1. This was repeated for plates 2 to 7 and the filter. Rectangular ROI was also taken to assess base accounts. Gross accounts were corrected for base activity and adjusted to accounts per minute (cpm).

Aerosol performance is characterized in the table in terms of fine particle fraction (FPF) 1 ie% delivered dose with a particle size <5.8 μιτι, mean aerodynamic mass diameter (MMAD), geometric standard deviation ( GSD) and the nebulization distribution time. CEBUD Preparation

The expelled contents of five Pulmicort respules (1 mg / mL) were combined together. Captisol® (165 mg) on a dry basis was added by Respule used to the combined contents of the commercial suspension to provide a Captisol concentration of about 7.5 wt%.

The mixture was rapidly centrifuged to disperse and dissolve Captisol®. It is then placed in a cylinder bed mixer and allowed to mix for two to four or several hours. Aliquots of the equilibrated mixtures were used to recover any budesonide retained in the original Respule container, and combined together. After visually checking that all suspended solids had dissolved, the required volume of 99m Tc-D5PA / saline solution (provided by Medical Physical Department, UHW) was added. Then about 180 μΙ of the radiolabelling solution was added to the rapidly centrifuged Captisol-Enabled® Budesonide Inhalation Solution.

EXAMPLE 23

The determination of the phase solubility curve for corticosteroid dissolution with SAE-CD.

The solubility of SAECD-containing corticosteroid solutions was determined by HPLC chromatography of aliquots of equilibrated filtered or centrifuged corticosteroid solutions as follows. SAE-CD / steroid solutions were prepared by weighing dry SAE-CD solids (to provide 0.04 molar) and excess steroid drug (6 mg / mL) together in a screw-capped vial. One volume of water was aliquoted for each vial (separate vial for each steroid). Intrinsic solubility was determined by weighing excess steroid (6 mg / mL) and adding a volume of water in the absence of CD. The vials were capped, initially centrifuged and sonicated. The vials were then placed in a cylinder mixer (model SRT2; Manufacturer: Stuart Scientific; Serial Number: R000100052) or oscillator / mixer (LabQuake Model; Manufacturer: Barnstead / Thermolyne; serial number 1104010438202). Larger excesses of solid steroid (up to 10 mg / mL) were then added to any vial where the liquid contents clarified overnight (eg prednisolone, hydrocortisone, and prednisone). Samples were laminated and mixed on the cylinder or oscillator for 72 hours. At various times during equilibration, the samples were additionally centrifuged or sonicated rapidly (up to 30 minutes). After the designated equilibration time, samples were filtered (0.22 μm, 25 mm, Duropore - PVDF, Millipore manufacturer) into clear vials except for the intrinsic solubility sample for Beclomethasone Dipropionate which was centrifuged and the supernatant transferred to a clear vial. Samples were analyzed by conventional HPLC methods.

EXAMPLE 24

Preparation of clear liquid formulations containing SAE-CD, budesonide and salmeterol xinafoate. Such a formulation may be prepared according to other included examples containing a combination of corticosteroids, SAE-CD and a second therapeutic agent.

EXAMPLE 25

Preparation of clear liquid formulations containing SASE-CD, budesonides and albuterol sulfate.

A stock solution containing CAPTISOL (40.0 g), water (1 L), citric acid (387.6 mg), sodium citrate (519.6 mg), EDTA (120 mg), and NaCl (6.36 mg) was prepared by mixing the components together.

Budesonide (37.5) and albuterol sulfate (150 mg) were added to an aliquot (150 ml) of the stock solution and mixed in a cylinder mixer at room temperature until dissolution of all components. The final solution was clear, however it can be filtered if necessary. The final concentration of components in the formulation was as follows: CAPTISOL (0.018 M); budesonide (5.9 mM or 254 pg / ml); and albuterol sulfate (1 mg / ml).

EXAMPLE 26

Droplet size distribution characterization of an aerosolized solution using a cascade impactor.

The droplet size distribution of an aerosolized solution of the invention was characterized using an NGI cascade impactor. Approximately 0.5 mL of the 1000 pg / mL was placed in a nebulizer such as AERONEB GO. The vacuum pump associated with the impactor has been started. The nebulizer nozzle was positioned in the center of the USP induction port and sealed to it with paraffin. The nebulizer was turned on until no more steam was visible. The vacuum was turned off and the impactor disassembled. Collection cups at each stage were extracted with known volumes of HPLC mobile phase and assayed for budesonide. The cumulative amount of budesonide at each stage was quantified. The percentage of drug leaving the nebulizer was 81%, and the percentage of drug in the fine particle fraction (<5 pm) was 66%.

Example 27

The determination of total drug output and drug output rate of a liquid-containing nebulizer of the invention.

The dose collection apparatus was constructed with a 300 ml glass filter unit of the type used for mobile HPLC filtering phases. A specially manufactured Plexiglas lid covered the reservoir and had an opening to allow aerosol into the reservoir. The reservoir tapered toward a fiberglass filter supported by a metal mesh. The mesh was contained in a conical glass housing that ended in a glass tube, which was connected to a flow controller and vacuum pump. The reservoir and filter support housing were attached to each other. Two filters were sandwiched together in the apparatus to collect the emitted aerosol. This was necessary to avoid filter saturation, which may result in filter wear and subsequent loss of drug in the vacuum, and changes in air flow rate during the aerosol collection course. Nebulizer termination was judged by intermittent aerosol output and / or a change in nebulizer noise release. To prevent the loss of nebulized budesonide to the atmosphere, air was extracted from inside the filter faster than it was ejected from the nebulizers. Visually confirming that no aerosol escaped the coasts of any nebulizer, a flow rate of 15 + 5% l / min was found to be satisfactory. This was regulated by a TPK flow controller (Copley Instruments, 4312) and vacuum pump, and confirmed prior to each experiment using a calibrated flow meter.

EXAMPLE 28

Preparation of a liquid formulation comprising SAE-CD and budesonide, optionally containing Tween.

A 3 mM citrate buffer at pH 4.5 was added to 2 grams of CAPTISOL and 25 mg budesonides in a serum vial to make up the final volume of 10 mL. The suspension was well mixed by centrifugation and sonication. A 20% stock solution of CAPTISOL without budesonide was also prepared in 3 mL citrate buffer. These mixtures, together with the buffer, were sealed in separate vials and autoclaved using a 20 minute hold on a 121 ° C cycle. HPLC analysis of the clear budesonide solution showed that the concentration was 2100 pg / mL. The 20% CAPTISOL stock solution was used to dilute the sample to 2000 pg / mL. A portion of the above resulting solution was optionally diluted with an equal volume of 3 mM citrate buffer. HPLC analysis showed that the final concentration was 990 pg budesonide / mL.

Tween may be added to the above solution as follows. A 0.02% Tween solution was prepared with the autoclaved solution buffer only to form a Tween stock solution for use as a diluent for the above solutions. Dilutions to 10% captisol / 1 mg / mL budesonide were made by weight. Approximately 9 grams of 20% captisol / 2000 pg / mL were mixed with ~ 9 grams of autoclaved solution only buffer or autoclaved buffer / 0.02% Tween solution. These solutions were well mixed, filtered and retested by HPLC.

Budesonide concentrations of the above formulations were found to be 986 Mg / ml for Tween free solution and 962 pg / ml for Tween solution.

Solutions can be nebulized with any nebulizer; however, with an AERx nebulizer, an initial sample volume of 50 μl can be used. Administration of this solution with the nebuliser makes it practicable for a therapeutic dose to be administered to a patient in a single jet (a single total inhalation by a patient) by nebulization.

EXAMPLE 29

Preparation and dissolution of a lyophilized formulation comprising SAE-CD and budesonide.

An excess of 3.5 mg / mL budesonide was added to 3 L of 30% Captisol in 3 mM citrate buffer containing 0.1 mg / mL ED-TA. After mixing for 2 days, an additional 1 mg / mL budesonide was added and equilibrated for a further 4 days. The preparation was filtered through a 0.22 μ Durapore filter and placed in three stainless steel trays in a freeze dryer. The solution was frozen at -30 ° C for one hour and lyophilized for 30 hours to essentially remove all water. The lyophil was made into powder, sieved and the powder transferred to a plastic bottle. The final composition contained 8.2 mg budesonide per gram of powder.

When approximately 65 mg of powder was added to 2 mL of water, an essentially clear solution containing the same amount of budesonide as in the reference suspension product was readily obtained.

Example 30

Preparation of an aqueous liquid formulation comprising SAE-CD, ethanol and budesonides.

Captisol / ethanol solutions were prepared by fabricating a 22.2% (-0.1 M) weight / volume stock captisol solution that was diluted with ethanol or water in varying amounts to create four solutions of 0, 1, 2.5% ethanol and about 20 wt% Captisol. The captisol / ethanol / budesonide solutions were prepared by adding dry budesonide (2.5 mg / mL) to one volume of the prepared captisol / ethanol solutions and then equilibrating in a Labquake for 72 hours. These solutions were filtered (Durapore syringe filters) and analyzed by HPLC to determine the concentration (µg / ml) of budesonide dissolved in the formulation.

EXAMPLE 31

An in vivo evaluation of a dosage form according to the invention was conducted by performing a pharmacokinetic analysis on budesonide following administration of the nebulized dosage form.

A four-dog crossover study to compare pulmonary distribution of budesonide by Pulmicort Respules®, and a Captisol-Enabled® budesonide formulation using a Pari LC air jet nebulizer was conducted. The purpose of the study was to determine, by HPLC-MS / MS analysis, the budesonide pharmacokinetics of plasma following nebulization of a budesonide suspension (Pulmicort Respules®, AstraZeneca, reference formulation) and a plasma inhalation solution. budesonide Captisol-Enabled® (test formulation) in healthy dogs. Dosing was conducted using a Pari LC Star air jet nebulizer and anesthetic masks.

Study dosage forms consisted of: 1) 1 mg budesonide as two 2 mL χ 0.25 mg / mL Pulmicort Respules®; or 2) 1 mg budesonide as two 2 mL χ 0.25 mg / mL Pulmicort Respules to which 5% weight / volume Captisol® was added.

Prior to dosing, two capsules containing activated charcoal followed by approximately 30 mL of water were administered to each dog to block oral absorption of budesonide. Each dog received each of the study administrations one week apart in a randomized manner. The administration time was the same for each formulation (23.9 min for the test formulation and 23.4 min for the reference). Blood was collected periodically for up to 8 hours, plasma was isolated and stored at -70 ° C until analysis. After each administration, the nebulizer and test solution container were tested for residual budesonide to determine the amount of drug delivered.

Example 32

To investigate how the incorporation of 5 wt% Captisol in impact performance of Pulmicort Respules of different types of nebulizers.

The emitted dose of budesonide from four different nebulizers (PARI LC PLUS (air jet), OMRON MICROAIR NE-U22, AIRSEP MYSTIQUE (ultrasonic), AEROGEN AERONEB) was determined. The package supplement-approved Pari air jet system was used as the benchmark for judging the performance of other nebulizers. The emitted dose was from 1.25 to 3.7 times higher when Captisol was added to the budesonide suspension. The emitted dose (ED) was determined:

1) Extracting the nebulized formulations through a 300 ml glass filter device at 15 l / min, and collecting the drug on double or triple layers of intense fiberglass filter and the inner walls. .

2) Adding the amount of budesonide over the cascade impactor stages after nebulization.

The results are detailed below. (ND stands for "undetermined).

All documents cited herein are each incorporated by reference herein in their entirety. The above is a detailed description of particular embodiments of the invention. It will be appreciated that while specific embodiments of the invention have been described herein for illustration purposes, various modifications may be made without departing from the spirit and scope of the invention. Therefore, the invention is not limited except by the appended claims. All embodiments described and claimed herein may be made and performed without undue experimentation having regard to the present disclosure.

Claims (20)

1. Use of a liquid formulation comprising an aqueous liquid medium, a sulfoalkyl ether cyclodextrin (SAE-CD) and a corticosteroid dosage dissolved therein, characterized in that it is for the preparation of a medicament for treating a disease or airway disorder in a patient in need thereof, wherein the formulation is administered by inhalation to the patient, and wherein the formulation provides an enhanced pharmacokinetic profile over a suspension-based formulation. administered under similar conditions. 2. A system characterized in that it comprises: a sprayer equipped with a reservoir; and an aqueous liquid formulation comprising an aqueous liquid solubility enhancer medium and a corticosteroid dose, wherein during nebulization of the formulation the nebulizer provides a percentage reduction in the rate of increasing corticosteroid concentration in a reservoir formulation when compared to the increasing concentration rate of a nebulized suspension based formulation with the nebulizer under similar conditions. Use according to claim 1, characterized in that the corticosteroid dose is present in an amount sufficient to provide an average plasma AUCt of 160-1600 pg * h / ml, and wherein the molar ratio SAE-CD for corticosteroids is greater than 10: 1. Use according to claim 1, characterized in that the formulation provides a plasma AUCt of 150-1600 pg * h / ml for the corticosteroid. Use according to claim 1, characterized in that the formulation comprises at least 25 μg corticosteroid, and wherein the formulation provides a normalized plasma AUCt for the corticosteroid dose of at least 6 (pg * h / ml) / μg corticosteroid. Use according to claim 1, characterized in that the formulation comprises at least 25 μg corticosteroid, and wherein the formulation provides a normalized plasma AUCt for the corticosteroid dose of at least 8 (pg * h / ml) / μρ of corticosteroids. An invention according to any one of claims 1 to 6, characterized in that cyclodextrin is a compound of Formula I: <i> formula see original document page 159 </i> Formula I wherein: η is 4, 5 or 6; R1, R2, R3, R4, Rs, Re> R7, Re and Rg are each independently -O- or a group -0- (C2 - Οβ alkylene) -SO3 ", where at least one of R1 - R9 is independently a group -0- (C2 - β-alkylene) -SO3 ", a group -O- (CH2) mSOa", where m is from 2 to 6, OCH2CH2CH2SO3, "or -0CH2CH2CH2CH2SO3"; and S1 S2, S3, S4, S5, S6, S7, Se and Sg are each independently a pharmaceutically acceptable cation. An invention according to any one of claims 1 to 6, characterized in that cyclodextrin is a compound of Formula II (SAEx-a-CD), wherein "x" ranges from 1 to 18; of Formula III (SAEy-p-CD), wherein "y" ranges from 1 to 21; or of Formula IV (SAEz-y-CD), wherein "z" ranges from -1 to 24, and where "SAE" represents a sulfoalkyl ether substituent, and the values "x", "y" and "z "represent the average degree of substitution in terms of the number of sulfoalkyl ether groups per CD molecule. Use according to claim 1, characterized in that the Cmax provided by the corticosteroid formulation is at least 1.5 times higher than the Cmax provided by the suspension-based formulation when the corticosteroid dose in the formulation is about 2 times lower than the dose in suspension. Use according to claim 1, characterized in that the formulation provides a Cmax (pg / ml) of 1,600 to 1,800 on a non-standard dose basis. Use according to claim 1, characterized in that, on the normalized basis of the nominal corticosteroid dose, the Cmax provided by the corticosteroid formulation is at least 1.7 times greater than the Cmax provided by the corticosteroid formulation. in suspension when the corticosteroid dose in the formulation and the suspension are approximately the same. Use according to claim 1, characterized in that the formulation provides an AUQnf (pg * h / ml) of 250 to 2,500 on a non-standard dose basis. Use according to claim 1, characterized in that, on the non-standard corticosteroid dose basis, the AUCinf provided by the corticosteroid formulation is 1.5 to 3.5 times higher than the AUCinf provided by the suspension-based formulation when the corticosteroid dose in the formulation and the suspension are approximately the same. Use according to claim 1, characterized in that the AUQnf provided by the corticosteroid formulation is at least 1.5 times higher than the AUQnf provided by the suspension-based formulation when the corticosteroid dose in the formulation is about 2 times lower than the dose in suspension. Use according to claim 1, characterized in that the formulation provides an AUC0-S h (pg * h / ml) of 2,000 to 3,000 on a non-standard corticosteroid dose basis. An invention according to any one of claims 1 to 6, characterized in that the corticosteroid is budesonide. An invention according to any one of claims 1 to 6, characterized in that the corticosteroid is selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyryl ciclesonide, flunisolid, propionate fluticasone, fluticasone furoate, mometasone furoate, icometasone inlay, thixocortol 21 pivalate, and triamcinolone acetonide. An invention according to any one of claims 1 to 6, characterized in that the formulation is administered with a nebulizer selected from the group consisting of an air jet nebulizer, ultrasonic nebulizer, electronic nebulizer, membrane nebulizer. in the vibratory, vibratory mesh nebulizer, vibratory plate nebulizer, a nebulizer comprising a vibration generator and an aqueous chamber, and a nebulizer comprising a nozzle arrangement. 19. Method for the preparation of a corticosteroid formulation, characterized in that it comprises mixing with high shear a corticosteroid, SAE-CD, and an aqueous liquid medium, in which SAE-CD is present in an amount enough to dissolve the corticosteroid. Method according to claim 19, characterized in that the high shear mixture is conducted with a sonicator, narrow gauge syringe (s), mixer / homogenizer, rotor-stator mixer, or mixer. of sawtooth.